Pure drug nanomedicines - where we are?

Abstract

Pure drug nanomedicines (PDNs) encompass active pharmaceutical ingredients (APIs), including macromolecules, biological compounds, and functional components. They overcome research barriers and conversion thresholds associated with nanocarriers, offering advantages such as high drug loading capacity, synergistic treatment effects, and environmentally friendly production methods. This review provides a comprehensive overview of the latest advancements in PDNs, focusing on their essential components, design theories, and manufacturing techniques. The physicochemical properties and in vivo behaviors of PDNs are thoroughly analyzed to gain an in-depth understanding of their systematic characteristics. The review introduces currently approved PDN products and further explores the opportunities and challenges in expanding their depth and breadth of application. Drug nanocrystals, drug-drug cocrystals (DDCs), antibody-drug conjugates (ADCs), and nanobodies represent the successful commercialization and widespread utilization of PDNs across various disease domains. Self-assembled pure drug nanoparticles (SAPDNPs), a next-generation product, still require extensive translational research. Challenges persist in transitioning from laboratory-scale production to mass manufacturing and overcoming the conversion threshold from laboratory findings to clinical applications.

Keywords

Pure drug nanomedicines / Drug nanocrystals / Drug-drug cocrystals / Antibody-drug conjugates / Drug nanoparticles / Nanobodies

References

[1] Ji B, Wei MJ, Yang B. Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy. Theranostics. 2022; 12(1): 434-458. https://doi.org/10.7150/thno.67300.

[2] Qian X, Xu XX, Wu Y, et al. Strategies of engineering nanomedicines for tumor retention. J Control Release. 2022; 346:193-211. https://doi.org/10.1016/j.jconrel.2022.04.006.

[3] Yang KK, Yang ZQ, Yu GC, et al. Polyprodrug nanomedicines: an emerging paradigm for cancer therapy. J Adv Mater. 2022; 34(6):2107434. https://doi.org/10.1002/adma.202107434.

[4] Li JC, Luo Y, Pu KY. Electromagnetic nanomedicines for combinational cancer immunotherapy. Angew Chem Int Ed Engl. 2021; 60(23):12682-12705. https://doi.org/10.1002/anie.202008386.

[5] Wagner V, Dullaart A, Bock AK, et al.The emerging nanomedicine landscape. Nat Biotechnol. 2006; 24(10):1211-1217. https://doi.org/10.1038/s41591-022-02061-1.

[6] Nance E. Careers in nanomedicine and drug delivery. Adv Drug Deliv Rev. 2019; 144:180-189. https://doi.org/10.1016/j.addr.2019.06.009.

[7] Stathopoulos GP, Antoniou D, Dimitroulis J, et al. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann Oncol. 2010; 21;(11):2227-2232. https://doi.org/10.1093/annonc/mdq234.

[8] Cabral H, Miyata K, Osada K, et al. Block copolymer micelles in nanomedicine applications. Chem Rev. 2018; 118(14):6844-6892. https://doi.org/10.1021/acs.chemrev.8b00199.

[9] McGuckin MB, Wang J, Ghanma R, et al. Nanocrystals as a master key to deliver hydrophobic drugs via multiple administration routes. J Control Release. 2022; 345:334-353. https://doi.org/10.1016/j.jconrel.2022.03.012.

[10] Min Y, Caster JM, Eblan MJ, et al.Clinical translation of nanomedicine. Chem Rev. 2015; 115(19):11147-11190. https://doi.org/10.1021/acs.chemrev.5b00116.

[11] Koklesova L, Jakubikova J, Cholujova D, et al. Phytochemical-based nanodrugs going beyond the state-of-the-art in cancer management—Targeting cancer stem cells in the framework of predictive, preventive, personalized medicine. Front Pharmacol. 2023;14:1121950. https://doi.org/10.3389/fphar.2023.1121950.

[12] Shah S, Dhawan V, Holm R, et al. Liposomes: advancements and innovation in the manufacturing process. Adv Drug Deliv Rev. 2020;154-155:102-122. https://doi.org/10.1016/j.addr.2020.07.002.

[13] Younis MA, Tawfeek HM, Abdellatif AAH, et al. Clinical translation of nanomedicines: challenges, opportunities, and keys. Adv Drug Deliv Rev. 2022;181:114083. https://doi.org/10.1016/j.addr.2021.114083.

[14] Mignani S, Shi XY, Guidolin K, et al. Clinical diagonal translation of nanoparticles: case studies in dendrimer nanomedicine. J Control Release. 2021; 337:356-370. https://doi.org/10.1016/j.jconrel.2021.07.036.

[15] Sercombe L, Veerati T, Moheimani F, et al. Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015; 6(1): 286. https://doi.org/10.3389/fphar.2015.00286.

[16] Karaosmanoglu S, Zhou MJ, Shi BY, et al. Carrier-free nanodrugs for safe and effective cancer treatment. J Control Release. 2021; 329:805-832. https://doi.org/10.1016/j.jconrel.2020.10.014.

[17] Huang L, Zhao SJ, Fang F, et al. Advances and perspectives in carrier-free nanodrugs for cancer chemo-monotherapy and combination therapy. Biomaterials. 2021;268:120557. https://doi.org/10.1016/j.biomaterials.2020.120557.

[18] Khatib I, Khanal D, Ruan J, et al. Ciprofloxacin nanocrystals liposomal powders for controlled drug release via inhalation. Int J Pharm. 2019; 566:641-651. https://doi.org/10.1016/j.ijpharm.2019.05.068.

[19] Lv YJ, Wu W, Corpstein CD, et al. Biological and intracellular fates of drug nanocrystals through different delivery routes: recent development enabled by bioimaging and PK modeling. Adv Drug Deliv Rev. 2022;188:114466. https://doi.org/10.1016/j.addr.2022.114466.

[20] Lu JR, Jiang G. The journey of CAR-T therapy in hematological malignancies. Mol Cancer. 2022;21:194. https://doi.org/10.1186/s12943-022-01663-0.

[21] Germain M, Caputo F, Metcalfe S, et al. Delivering the power of nanomedicine to patients today. J Control Release. 2020; 326:164-171. https://doi.org/10.1016/j.jconrel.2020.07.007.

[22] Tian ZH, Zhao Y, Mai YP, et al. Nanocrystals with different stabilizers overcome the mucus and epithelial barriers for oral delivery of multicomponent Bufadienolides. Int J Pharm. 2022;616:121522. https://doi.org/10.1016/j.ijpharm.2022.121522.

[23] Raza F, Zafar H, You X, et al. Cancer nanomedicine: focus on recent developments and self-assembled peptide nanocarriers. J Mater Chem B. 2019; 7(48):7639-7655. https://doi.org/10.1039/C9TB01842E.

[24] Falanga A, Galdiero S. Peptide chemistry encounters nanomedicine: recent applications and upcoming scenarios in cancer. Future Med Chem. 2018; 10(16):1877-1880. https://doi.org/10.4155/fmc-2018-0182.

[25] Ying YW, Tang Q, Han D, et al. Nucleic acid nanotechnology for diagnostics and therapeutics in acute kidney injury. Int J Mol Sci. 2022; 23(6):3093. https://doi.org/10.3390/ijms23063093.

[26] Wang YT, Xuan JJ, Zhao GC, et al. Improving stability and oral bioavailability of hydroxycamptothecin via nanocrystals in microparticles (NCs/MPs) technology. Int J Pharm. 2021;604:120729. https://doi.org/10.1016/j.ijpharm.2021.120729.

[27] Da Rocha NP, De Souza A, Yukuyama MN, et al. Highly water-soluble dapsone nanocrystals: towards innovative preparations for an undermined drug. Int J Pharm. 2023;630:122428. https://doi.org/10.1016/j.ijpharm.2022.122428.

[28] Dave RS, Goostrey TC, Ziolkowska M, et al. Ocular drug delivery to the anterior segment using nanocarriers: a mucoadhesive/mucopenetrative perspective. J Control Release. 2021; 336:71-88. https://doi.org/10.1016/j.jconrel.2021.06.011.

[29] Maged A, Mahmoud AA, Ghorab MM. Nano spray drying technique as a novel approach to formulate stable econazole nitrate nanosuspension formulations for ocular use. Mol Pharm. 2016; 13(9):2951-2965. https://doi.org/10.1021/acs.molpharmaceut.6b00167.

[30] Peltonen L. Practical guidelines for the characterization and quality control of pure drug nanoparticles and nano-cocrystals in the pharmaceutical industry. Adv Drug Deliv Rev. 2018; 131:101-115. https://doi.org/10.1016/j.addr.2018.06.009.

[31] Koseki Y, Ikuta Y, Taemaitree F, et al. Fabrication of size-controlled SN-38 pure drug nanocrystals through an ultrasound-assisted reprecipitation method toward efficient drug delivery for cancer treatment. J Cryst Growth. 2021;572:126265. https://doi.org/10.1016/j.jcrysgro.2021.126265.

[32] Mei H, Cai SS, Huang D, et al. Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy: from intrinsic physicochemical properties to external modification. Bioact Mater. 2022; 8:220-240. https://doi.org/10.1016/j.bioactmat.2021.06.035.

[33] Kim MR, Lee S, Yoon J, et al. Preparations of MgO nanoparticles by a poly(acrylic acid)s template-assisted method and photovoltaic performances of dye-sensitized solar cells based on MgO interlayer. ACS Appl Mater Interfaces. 2023; 16:19957-19967. https://doi.org/10.1021/acsami.3c13076.

[34] Zheng R, Yang J, Mamuti M, et al. Controllable self-assembly of peptide-cyanine conjugates in vivo as fine-tunable theranostics. Angew Chem Int Ed Engl. 2021; 60(14):7809-7819. https://doi.org/10.1002/anie.202015126.

[35] Zhang XQ, Cai SS, He YM, et al. Enzyme-triggered deshielding of nanoparticles and positive-charge mediated lysosomal escape for chemo/photo-combination therapy. J Mater Chem B. 2019; 7(31):4758-4762. https://doi.org/10.1039/C9TB00685K.

[36] Hu H, Feng W, Qian XQ, et al. Emerging nanomedicine‐enabled/enhanced nanodynamic therapies beyond traditional photodynamics. Adv Mater. 2021; 33(12):2005062. https://doi.org/10.1002/adma.202005062.

[37] Huang LF, Hu SY, Fu YN, et al. Multicomponent carrier-free nanodrugs for cancer treatment. J Mater Chem B. 2022; 10(47):9735-9754. https://doi.org/10.1039/D2TB02025D.

[38] Peng F, Liu J, Chen JJ, et al. Nanocrystals slow-releasing ropivacaine and doxorubicin to synergistically suppress tumor recurrence and relieve postoperative pain. ACS Nano. 2023; 17(20):20135-20152. https://doi.org/10.1021/acsnano.3c05831.

[39] Zhang CY, Long L, Xiong Y, et al.Gout therapeutics and drug delivery. ACS Appl Mater Interfaces. 2019; 11:9872-9883. https://doi.org/10.1021/acsami.8b22336.

[40] Yang MY, Zhao RR, Fang YF, et al. Carrier-free nanodrug: a novel strategy of cancer diagnosis and synergistic therapy. Int J Pharm. 2019;570:118663. https://doi.org/10.1016/j.ijpharm.2019.118663.

[41] Wang H, Lin F, Wu Y, et al. Carrier-free nanodrug based on co-assembly of methylprednisolone dimer and rutin for combined treatment of spinal cord injury. ACS Nano. 2023; 17(13):12176-12187. https://doi.org/10.1021/acsnano.3c00360.

[42] Quinlan JA, Inglut CT, Srivastava P, et al. Carrier‐free, amorphous verteporfin nanodrug for enhanced potodynamic cancer therapy and brain drug delivery. Adv Sci. 2024; 11(17):2302872. https://doi.org/10.1002/advs.202302872.

[43] Zhuang WR, Wang Y, Cui PF, et al. Applications of π-π stacking interactions in the design of drug-delivery systems. J Control Release. 2019; 294:311-326. https://doi.org/10.1016/j.jconrel.2018.12.014.

[44] Hwang D, Ramsey JD, Kabanov AV. Polymeric micelles for the delivery of poorly soluble drugs: from nanoformulation to clinical approval. Adv Drug Deliv Rev. 2020; 156:80-118. https://doi.org/10.1016/j.addr.2020.09.009.

[45] Zhao Z, Ukidve A, Krishnan V, et al. Effect of physicochemical and surface properties on in vivo fate of drug nanocarriers. Adv Drug Deliv Rev. 2019; 143:3-21. https://doi.org/10.1016/j.addr.2019.01.002.

[46] Li XT, Gu J, Xiao QQ, et al. Liposomal codelivery of inflammation inhibitor and collagen protector to the plaque for effective anti-atherosclerosis. Chin Chem Lett. 2023; 34(1):107483. https://doi.org/10.1016/j.cclet.2022.04.081.

[47] Boafo GF, Shi YJ, Xiao QQ, et al. Targeted co-delivery of daunorubicin and cytarabine based on the hyaluronic acid prodrug modified liposomes. Chin Chem Lett. 2022; 33(10):4600-4604. https://doi.org/10.1016/j.cclet.2022.04.033.

[48] Chen WZ, Zhou SS, Ge L, et al. Translatable high drug loading drug delivery systems based on biocompatible polymer nanocarriers. Biomacromolecules. 2018; 19(6):1732-1745. https://doi.org/10.1021/acs.biomac.8b00218.

[49] Shen SH, Wu YS, Liu YC, et al. High drug-loading nanomedicines: progress, current status, and prospects. Int J Nanomed. 2017; 12:4085-4109. https://doi.org/10.2147/IJN.S132780.

[50] Bai M, Yang MS, Gong JH, et al. Progress and principle of drug nanocrystals for tumor targeted delivery. AAPS PharmSciTech. 2022; 23(1):41. https://doi.org/10.1208/s12249-021-02200-w.

[51] Mao YL, Liu J, Shi TY, et al. A novel self-assembly nanocrystal as lymph node-targeting delivery system: higher activity of lymph node targeting and longer efficacy against lymphatic metastasis. AAPS PharmSciTech. 2019; 20(7):292. https://doi.org/10.1208/s12249-019-1447-3.

[52] Barrett JA, Yang W, Skolnik SM, et al. Discovery solubility measurement and assessment of small molecules with drug development in mind. Drug Discov Today. 2022; 27(5):1315-1325. https://doi.org/10.1016/j.drudis.2022.01.017.

[53] Porat D, Dahan A. Active intestinal drug absorption and the solubility-permeability interplay. Int J Pharm. 2018; 537(1-2):84-93. https://doi.org/10.1016/j.ijpharm.2017.10.058.

[54] Zhang X, Sun Y, Cheng Y, et al. Biopharmaceutics classification evaluation for paris saponin VII. Chin J Nat Med. 2020; 18(9):714-720. https://doi.org/10.1016/S1875-5364(20)60010-3.

[55] Li JJ, Cheng L, Shen G, et al. Improved stability and oral bioavailability of Ganneng dropping pills following transforming lignans of herpetospermum caudigerum into nanosuspensions. Chin J Nat Med. 2018; 16(1):70-80. https://doi.org/10.1016/S1875-5364(18)30031-1.

[56] Chien ST, Suydam IT, Woodrow KA. Prodrug approaches for the development of a long-acting drug delivery systems. Adv Drug Deliv Rev. 2023;198:114860. https://doi.org/10.1016/j.addr.2023.114860.

[57] Zhang YZ, Cui HG, Zhang RQ, et al. Nanoparticulation of prodrug into medicines for vancer therapy. Adv Sci. 2021; 8(18):2101454. https://doi.org/10.1002/advs.202101454.

[58] Zhao HB, Yu J, Zhang RS, et al. Doxorubicin prodrug-based nanomedicines for the treatment of cancer. Eur J Med Chem. 2023;258:115612. https://doi.org/10.1016/j.ejmech.2023.115612.

[59] Peltonen L, Hirvonen J. Drug nanocrystals-Versatile option for formulation of poorly soluble materials. Int J Pharm. 2018; 537(1-2):73-83. https://doi.org/10.1016/j.ijpharm.2017.12.005.

[60] Fontana F, Figueiredo P, Zhang P, et al. Production of pure drug nanocrystals and nano co-crystals by confinement methods. Adv Drug Deliv Rev. 2018; 131:3-21. https://doi.org/10.1016/j.addr.2018.05.002.

[61] Junghanns JUAH, Müller RH. Nanocrystal technology,drug delivery and clinical applications. Int J Nanomed. 2008; 3(3):295-309. https://doi.org/10.2147/IJN.S595.

[62] Pi JX, Wang SY, Li W, et al. A nano-cocrystal strategy to improve the dissolution rate and oral bioavailability of baicalein. Asian J Pharm Sci. 2019; 14(2):154-164. https://doi.org/10.1016/j.ajps.2018.04.009.

[63] Lu Y, Qi JP, Dong XC, et al. The in vivo fate of nanocrystals. Drug Discov Today. 2017; 22(4):744-750. https://doi.org/10.1016/j.drudis.2017.01.003.

[64] Parmar PK, Wadhawan J, Bansal AK. Pharmaceutical nanocrystals: a promising approach for improved topical drug delivery. Drug Discov Today. 2021; 26(10):2329-2349. https://doi.org/10.1016/j.drudis.2021.07.010.

[65] Shen BD, Shen CY, Zhu WF, et al. The contribution of absorption of integral nanocrystals to enhancement of oral bioavailability of quercetin. Acta Pharm Sin B. 2021; 11(4):978-988. https://doi.org/10.1016/j.apsb.2021.02.015.

[66] Gao L, Liu GY, Ma JL, et al. Drug nanocrystals: in vivo performances. J Control Release. 2012; 160(3):418-430. https://doi.org/10.1016/j.jconrel.2012.03.013.

[67] Xiao QQ, Li XT, Liu C, et al. Liposome-based anchoring and core-encapsulation for combinatorial cancer therapy. Chin Chem Lett. 2022; 33(9):4191-4196. https://doi.org/10.1016/j.cclet.2022.01.083.

[68] Magar KT, Boafo GF, LiXT, et al.Liposome-based delivery of biological drugs. Chin Chem Lett. 2022; 33(2):587-596. https://doi.org/10.1016/j.cclet.2021.08.020.

[69] Allen C. The question of toxicity of nanomaterials and nanoparticles. J Control Release. 2019;304:288. https://doi.org/10.1016/j.jconrel.2019.06.008.

[70] Miller MR, Poland CA. Nanotoxicology: the need for a human touch?. Small. 2020; 16(36):e2001516. https://doi.org/10.1002/smll.202001516.

[71] Cai XM, Liu X, Jiang J, et al. Molecular mechanisms, characterization methods, and utilities of nanoparticle biotransformation in nanosafety assessments. Small. 2020; 16(36):e1907663. https://doi.org/10.1002/smll.201907663.

[72] Alshehri R, Ilyas AM, Hasan A, et al. Carbon nanotubes in biomedical applications: factors, mechanisms, and remedies of toxicity. J Med Chem. 2016; 59(18):8149-8167. https://doi.org/10.1021/acs.jmedchem.5b01770.

[73] Yang S, Zhang TY, Ge YL, Cheng YP, et al. Sentinel supervised lung-on-a-chip: a new environmental toxicology platform for nanoplastic-induced lung injury. J Hazard Mater. 2023;458:131962. https://doi.org/10.1016/j.jhazmat.2023.131962.

[74] Ibrahim S, Albert AA, Seid AY, et al. Harmonizing tradition and technology: liposomal nanocarriers un- locking the power of natural herbs in Traditional Chinese Medicine. Chin J Nat Med. 2023; 22(1):1-3. https://doi: 10.1016/S1875-5364(24)60552-.

[75] Najahi-Missaoui W, Arnold RD, Cummings BS. Safe nanoparticles: are we there yet?. Int J Mol Sci. 2020; 22(1): 385. https://doi.org/10.3390/ijms22010385.

[76] Elsaesser A, Howard CV.Toxicology of nanoparticles. Adv Drug Deliv Rev. 2012; 64(2):129-137. https://doi.org/10.1016/j.addr.2011.09.001.

[77] Siivola KM, Burgum MJ, Suárez-Merino B, et al. A systematic quality evaluation and review of nanomaterial genotoxicity studies: a regulatory perspective. Part Fibre Toxicol. 2022; 19(1):59. https://doi.org/10.1186/s12989-022-00499-2.

[78] Jiang T, Lin YS, Amadei CA, et al. Comparative and mechanistic toxicity assessment of structure-dependent toxicity of carbon-based nanomaterials. J Hazard Mater. 2021;418:126282. https://doi.org/10.1016/j.jhazmat.2021.126282.

[79] Lu XF, Liu Y, Kong XJ, et al. Nanotoxicity: a growing need for study in the endocrine system. Small. 2013; 9(9-10):1654-1671. https://doi.org/10.1002/smll.201201517.

[80] Dhoble S, Wu TH, Kenry. Decoding nanomaterial‐biosystem interactions through machine learning. Angew Chem Int Ed Engl. 2024; 63(16):e202318380. https://doi.org/10.1002/anie.202318380.

[81] Liu QW, Fang YL, Xiong XH, et al. Ostwald ripening for designing time‐dependent crystal hydrogels. Angew Chem Int Ed. 2024; 63(17):e202320095. https://doi.org/10.1002/anie.202320095.

[82] Singh Y, Meher JG, Raval K, et al. Nanoemulsion: concepts, development and applications in drug delivery. J Control Release. 2017; 252:28-49. https://doi.org/10.1016/j.jconrel.2017.03.008.

[83] Zhang ZR, Wang ZN, He SN, et al. Redox reaction induced Ostwald ripening for size- and shape-focusing of palladium nanocrystals. Chem Sci. 2015; 6(9):5197-5203. https://doi.org/10.1039/C5SC01787D.

[84] Yang H, Kim H, Jung S, et al. Pharmaceutical strategies for stabilizing drug nanocrystals. Curr Pharm Des. 2018; 24(21):2362-2374. https://doi.org/10.2174/1381612824666180515125247.

[85] Alarcon R, Walter M, Paez M, et al. Ostwald ripening and antibacterial activity of silver nanoparticles capped by anti-inflammatory ligands. Nanomaterials. 2023; 13(3):428. https://doi.org/10.3390/nano13030428.

[86] Wang YC, Zheng Y, Zhang L, et al. Stability of nanosuspensions in drug delivery. J Control Release. 2013; 172(3):1126-1141. https://doi.org/10.1016/j.jconrel.2013.08.006.

[87] Möschwitzer J, Achleitner G, Pomper H, et al. Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology. Eur J Pharm Biopharm. 2004; 58(3):615-619. https://doi.org/10.1016/j.ejpb.2004.03.022.

[88] Halwani AA. Development of pharmaceutical nanomedicines: from the bench to the market. Pharmaceutics. 2022; 14(1):106. https://doi.org/10.3390/pharmaceutics14010106.

[89] Moghimi SM, Peer D, Langer R. Reshaping the future of nanopharmaceuticals: ad iudicium. ACS Nano. 2011; 5(11):8454-8458. https://doi.org/10.1021/nn2038252.

[90] Chen ML, John M, Lee SL, et al. Development considerations for nanocrystal drug products. AAPS J. 2017; 19(3):642-651. https://doi.org/10.1208/s12248-017-0064-x.

[91] Macedo LDO, Barbosa EJ, Löbenberg R, et al. Anti-inflammatory drug nanocrystals: state of art and regulatory perspective. Eur J Pharm Sci. 2021;158:105654. https://doi.org/10.1016/j.ejps.2020.105654.

[92] Duggan S.Caplacizumab: first global approval. Drugs. 2018; 78(15):1639-1642. https://doi.org/10.1007/s40265-018-0989-0.

[93] Fu ZW, Li SJ, Han SF, et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022; 7(1):93. https://doi.org/10.1038/s41392-022-00947-7.

[94] Do Pazo C, Nawaz K, Webster RM. The oncology market for antibody-drug conjugates. Nat Rev Drug Discov. 2021; 20(8):583-584. https://doi.org/10.1038/d41573-021-00054-2.

[95] Chia CSB. A patent review on FDA‐approved antibody‐drug conjugates, their linkers and drug payloads. ChemMedChem. 2022; 17(11):e202200032. https://doi.org/10.1002/cmdc.202200032.

[96] Allan J, Belz S, Hoeveler A, et al. Regulatory landscape of nanotechnology and nanoplastics from a global perspective. Regul Toxicol Pharmacol. 2021;122:104885. https://doi.org/10.1016/j.yrtph.2021.104885.

[97] Soares S, Sousa J, Pais A, et al. Nanomedicine: principles, properties, and regulatory issues. Front Chem. 2018; 6 :360. https://doi.org/10.3389/fchem.2018.00360.

[98] Office of the Commissioner. Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology, U. S. Food and Drug Administration (2016). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considering-whether-fda-regulated-product-involves-application-nanotechnology.

[99] Office. Center for Food Safety and Applied Nutrition Nanotechnology Programs, U. S. Food and Drug Administration.(2018). https://www.fda.gov/science-research/nanotechnology-programs-fda/center-food-safety-and-applied-nutrition-nanotechnology-programs.

[100] Fytianos G, Rahdar A, Kyzas GZ.Nanomaterials in cosmetics: recent updates. Nanomaterials. 2020;10:979. https://doi.org/10.3390/nano10050979.

[101] Dréno B, Alexis A, Chuberre B, et al. Safety of titanium dioxide nanoparticles in cosmetics. J Eur Acad Dermatol Venereol. 2019; 33(Suppl 7):34-46. https://doi.org/10.1111/jdv.15943.

[102] Meftahi A, Samyn P, Geravand SA, et al. Nanocelluloses as skin biocompatible materials for skincare, cosmetics, and healthcare: formulations, regulations, and emerging applications. Carbohydr Polym. 2022;278:118956. https://doi.org/10.1016/j.carbpol.2021.118956.

[103] Halamoda‐Kenzaoui B, Holzwarth U, Roebben G, et al. Mapping of the available standards against the regulatory needs for nanomedicines. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2019;11:e1531. https://doi.org/10.1002/wnan.1531.

[104] Hussain SM, Warheit DB, Ng SP, et al. At the crossroads of nanotoxicology in vitro : past achievements and current challenges. Toxicol Sci. 2015; 147(1):5-16. https://doi.org/10.1093/toxsci/kfv106.

[105] Souto EB, Blanco-Llamero C, Krambeck K, et al. Regulatory insights into nanomedicine and gene vaccine innovation: safety assessment, challenges, and regulatory perspectives. Acta Biomater. 2024; 180:1-17. https://doi.org/10.1016/j.actbio.2024.04.010.

[106] Wang YT, Li HN, Wang LC, et al. Mucoadhesive nanocrystal-in-microspheres with high drug loading capacity for bioavailability enhancement of silybin. Colloids Surf B Biointerfaces. 2021;198:111461. https://doi.org/10.1016/j.colsurfb.2020.111461.

[107] Marques MRC, Choo Q, Ashtikar M, et al. Nanomedicines - Tiny particles and big challenges. Adv Drug Deliv Rev. 2019;151-152:23-43. https://doi.org/10.1016/j.addr.2019.06.003.

[108] Joudeh N, Linke D. Nanoparticle classification, physicochemical properties, characterization, and applications: a comprehensive review for biologists. J Nanobiotechnol. 2022; 20(1):262. https://doi.org/10.1186/s12951-022-01477-8.

[109] Jamrógiewicz M, Milewska K, Mikolaszek B. Spectroscopic evaluation on pseudopolymorphs of sodium naproxen. Spectrochim Acta A Mol Biomol Spectrosc. 2021;261:120018. https://doi.org/10.1016/j.saa.2021.120018.

[110] Prasanna NS, Mitra J. Isolation and characterization of cellulose nanocrystals from Cucumis sativus peels. Carbohydr Polym. 2020;247:116706. https://doi.org/10.1016/j.carbpol.2020.116706.

[111] EMA. European Medicines Agency holds first scientific workshop on nanomedicines, European Medicines Agency (2018). . https://www.ema.europa.eu/en/news/european-medicines-agency-holds-first-scientific-workshop-nanomedicines (accessed January 1, 2023).

[112] Sainz V, Conniot J, Matos AI, et al.Regulatory aspects on nanomedicines. Biochem Biophys Res Commun. 2015; 468(3):504-510. https://doi.org/10.1016/j.bbrc.2015.08.023.

[113] Brenner S. Nanomedicine: promises and challenges for the future of public health. Int J Nanomedicine. 2010; 5:803-809. https://doi.org/10.2147/IJN.S13816.

[114] Tyagi P, Subramony JA. Nanotherapeutics in oral and parenteral drug delivery: key learnings and future outlooks as we think small. J Control Release. 2018; 272:159-168. https://doi.org/10.1016/j.jconrel.2018.01.009.

[115] He Y, Liang YM, Mak JCW, et al. Size effect of curcumin nanocrystals on dissolution, airway mucosa penetration, lung tissue distribution and absorption by pulmonary delivery. Colloids Surf B Biointerfaces. 2020;186:110703. https://doi.org/10.1016/j.colsurfb.2019.110703.

[116] Imono M, Uchiyama H, Yoshida S, et al. The elucidation of key factors for oral absorption enhancement of nanocrystal formulations: in vitro-in vivo correlation of nanocrystals. Eur J Pharm Biopharm. 2020; 146:84-92. https://doi.org/10.1016/j.ejpb.2019.12.002.

[117] Miao XQ, Li Y, Wang XQ, et al. Transport mechanism of coumarin 6 nanocrystals with two particle sizes in MDCKII monolayer and larval zebrafish. ACS Appl Mater Interfaces. 2016; 8(20):12620-12630. https://doi.org/10.1021/acsami.6b01680.

[118] Ryanodex--a new dantrolene formulation for malignant hyperthermia. Med Lett Drugs Ther. 2015; 57(1472):100.

[119] Lu Y, Lv YJ, Li TL.Hybrid drug nanocrystals. Adv Drug Deliv Rev. 2019; 143:115-133. https://doi.org/10.1016/j.addr.2019.06.006.

[120] Sheng YZ, Yu Q, Huang YP, et al. Pickering emulsions enhance oral bioavailability of curcumin nanocrystals: the effect of oil types. Pharmaceutics. 2023; 15(5):1341. https://doi.org/10.3390/pharmaceutics15051341.

[121] Farooq MA, Jabeen A, Wang B. Formulation, optimization, and characterization of whey protein isolate nanocrystals for celecoxib delivery. J Microencapsu. 2021; 38(5):314-323. https://doi.org/10.1080/02652048.2021.1915398.

[122] Fuhrmann k, Gauthier MA, Leroux JC.Targeting of injectable drug nanocrystals. Mol Pharmaceutics. 2014; 11(6):1762-1771. https://doi.org/10.1021/mp5001247.

[123] Mohammad IS, Hu HY, Yin LF, et al. Drug nanocrystals: fabrication methods and promising therapeutic applications. Int J Pharm. 2019; 562:187-202. https://doi.org/10.1016/j.ijpharm.2019.02.045.

[124] Möschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Int J Pharm. 2013; 453(1):142-156. https://doi.org/10.1016/j.ijpharm.2012.09.034.

[125] Wang YC, Liu ZP, Zhang DR, et al. Development and in vitro evaluation of deacety mycoepoxydiene nanosuspension. Colloids Surf B Biointerfaces. 2011; 83(2):189-197. https://doi.org/10.1016/j.colsurfb.2010.10.029.

[126] Sinha B, Müller RH, Möschwitze JP. Systematic investigation of the cavi-precipitation process for the production of ibuprofen nanocrystals. Int J Pharm. 2013; 458(2):315-323. https://doi.org/10.1016/j.ijpharm.2013.10.025.

[127] Girdhar A, Thakur P, Sheokand S, et al. Permeability behavior of nanocrystalline solid dispersion of dipyridamole generated using nanoCrySP technology. Pharmaceutics. 2018; 10(3):160. https://doi.org/10.3390/pharmaceutics10030160.

[128] Verma V, Ryan KM, Padrela L. Production and isolation of pharmaceutical drug nanoparticles. Int J Pharm. 2021;603:120708. https://doi.org/10.1016/j.ijpharm.2021.120708.

[129] Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46(1-3):3-26 https://doi.org/10.1016/S0169-409X(00)00129-0.

[130] He Y, Ye ZF, Liu XY, et al. Can machine learning predict drug nanocrystals?. J Control Release. 2020; 322:274-285. https://doi.org/10.1016/j.jconrel.2020.03.043.

[131] George M, Ghosh I. Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology. Eur J Pharm Sci. 2013; 48(1-2):142-152. https://doi.org/10.1016/j.ejps.2012.10.004.

[132] Blagden N, De Matas M, Gavan PT, et al. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev. 2007; 59(7):617-630. https://doi.org/10.1016/j.addr.2007.05.011.

[133] Zhou HY, Sabino J, Yang YF, et al. Tailor-made additives for melt-grown molecular crystals: why or why not?. Annu Rev Mater Res. 2023; 53:143-164. https://doi.org/10.1146/annurev-matsci-081720-112946.

[134] Zhang XH, Su ML, MengWH, et al. Trace polymer coated clarithromycin spherulites: formation mechanism, improvement in pharmaceutical properties and development of high-drug-loading direct compression tablets. Int J Pharm. 2024;654:123944. https://doi.org/10.1016/j.ijpharm.2024.123944.

[135] Yang Y, Zoulikha M, Xiao QQ, et al. Pulmonary endothelium-targeted nanoassembly of indomethacin and superoxide dismutase relieves lung inflammation. Acta Pharm Sin B. 2023; 13(11):4607-4620. https://doi.org/10.1016/j.apsb.2023.05.024.

[136] Li BB, Teng C, Yu HL, et al. Alleviating experimental pulmonary hypertension via co-delivering FoxO1 stimulus and apoptosis activator to hyperproliferating pulmonary arteries. Acta Pharm Sin B. 2023; 13(6):2369-2382. https://doi.org/10.1016/j.apsb.2022.12.002.

[137] Magar KT, Boafo GF, Zoulikha M, et al. Metal phenolic network-stabilized nanocrystals of andrographolide to alleviate macrophage-mediated inflammation in-vitro. Chin Chem Lett. 2023; 34(1):107453. https://doi.org/10.1016/j.cclet.2022.04.051.

[138] Mustan F, Politova-Brinkova N, Vinarov Z, et al. Interplay between bulk aggregates, surface properties and foam stability of nonionic surfactants. Adv Colloid Interface Sci. 2022;302:102618. https://doi.org/10.1016/j.cis.2022.102618.

[139] Zarrintaj P. Ramsey JD, Samadi A, et al. Poloxamer: a versatile tri-block copolymer for biomedical applications. Acta Biomater. 2020; 110:37-67. https://doi.org/10.1016/j.actbio.2020.04.028.

[140] Fu Q, Jin X, Zhang ZH, et al. Preparation and in vitro antitumor effects on MDA-MB-231 cells of niclosamide nanocrystals stabilized by poloxamer188 and PBS. Int J Pharm. 2020;584:119432. https://doi.org/10.1016/j.ijpharm.2020.119432.

[141] Park JJ, Meghani N, Choi JS, et al. Development and evaluation of decorated aceclofenac nanocrystals. Colloids Surf B Biointerfaces. 2016; 143:206-212. https://doi.org/10.1016/j.colsurfb.2016.03.022.

[142] Sharma S, Verma A, Pandey G, et al. Investigating the role of Pluronic-g-Cationic polyelectrolyte as functional stabilizer for nanocrystals: impact on Paclitaxel oral bioavailability and tumor growth. Acta Biomater. 2015; 26:169-183. https://doi.org/10.1016/j.actbio.2015.08.005.

[143] Zhang X, Dong W, Cheng HB, et al. Modulating intestinal mucus barrier for nanoparticles penetration by surfactants. Asian J Pharm Sci. 2019; 14:543-551. https://doi.org/10.1016/j.ajps.2018.09.002.

[144] Emilsson G, Liu K, Höök F, et al. The in vivo fate of polycatecholamine coated nanoparticles is determined by a fibrinogen enriched protein corona. ACS Nano. 2023; 17(24):24725-24742. https://doi.org/10.1021/acsnano.3c04968.

[145] Van Eerdenbrugh B, Vermant J, Martens JA, et al. A screening study of surface stabilization during the production of drug nanocrystals. J Pharm Sci. 2009; 98(6):2091-2103. https://doi.org/10.1002/jps.21563.

[146] Ghosh I, Schenck D, Bose S, et al. Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: effect of Vitamin E TPGS and nanocrystal particle size on oral absorption. Eur J Pharm Sci. 2012; 47(4):718-728. https://doi.org/10.1016/j.ejps.2012.08.011.

[147] Tuomela A, Hirvonen J, Peltonen L. Stabilizing agents for drug nanocrystals: effect on bioavailability. Pharmaceutics. 2016; 8(2):16. https://doi.org/10.3390/pharmaceutics8020016.

[148] Chen ZJ, Wu W, Lu Y. What is the future for nanocrystal-based drug-delivery systems?. Ther Deliv. 2020; 11(4):225-229. https://doi.org/10.4155/tde-2020-0016.

[149] Li XT, Zou JH, He ZS, et al. The interaction between particles and vascular endothelium in blood flow. Adv Drug Deliv Rev. 2024;207:115216. https://doi.org/10.1016/j.addr.2024.115216.

[150] Kong Y, Cai H, Xing H, et al. Pulmonary delivery alters the disposition of raloxifene in rats. J Pharm Pharmacol. 2020; 72(2):185-196. https://doi.org/10.1111/jphp.13201.

[151] Fu Q, Sun J, Zhang D, et al. Nimodipine nanocrystals for oral bioavailability improvement: preparation, characterization and pharmacokinetic studies. Colloids Surf B Biointerfaces. 2013; 109:161-166. https://doi.org/10.1016/j.colsurfb.2013.01.066.

[152] Tian ZH, Mai YP, Meng TT, et al. Nanocrystals for improving oral bioavailability of drugs: intestinal transport mechanisms and influencing factors. AAPS PharmSciTech. 2021; 22(5):179. https://doi.org/10.1208/s12249-021-02041-7.

[153] Manjunath K, Venkateswarlu V. Pharmacokinetics, tissue distribution and bioavailability of clozapine solid lipid nanoparticles after intravenous and intraduodenal administration. J Control Release. 2005; 107(2):215-228. https://doi.org/10.1016/j.jconrel.2005.06.006.

[154] Xia Q, Shen JQ, Ding HN, et al. Intravenous nanocrystals: fabrication, solidification, in vivo fate, and applications for cancer therapy. Expert Opin Drug Deliv. 2023; 20(11):1467-1488. https://doi.org/10.1080/17425247.2023.2268512.

[155] Wang X, Wu Z, Liu JP, et al. Particle morphology: an important factor affecting drug delivery by nanocarriers into solid tumors. Expert Opin Drug Deliv. 2018; 15(4):379-395. https://doi.org/10.1080/17425247.2018.1420051.

[156] Xin XF, Pei X, Yang X, et al. Rod‐shaped active drug particles enable efficient and safe gene delivery. Adv Sci. 2017; 4(11):1700324. https://doi.org/10.1002/advs.201700324.

[157] Zhou MJ, Zhang XJ, Yu CT, et al. Shape regulated anticancer activities and systematic toxicities of drug nanocrystals in vivo. Nanomedicine. 2016; 12(1):181-189. https://doi.org/10.1016/j.nano.2015.09.006.

[158] Weiss AM, Macke N, Zhang YF, et al. In vitro and in vivo analyses of the effects of source, length, and charge on the cytotoxicity and immunocompatibility of cellulose nanocrystals. ACS Biomater Sci Eng. 2021; 7:1450-1461. https://doi.org/10.1021/acsbiomaterials.0c01618.

[159] Qin MD, Xin JH, Han W, et al. Stabilizer-induced different in vivo behaviors for intramuscularly long-acting celecoxib nanocrystals. Int J Pharm. 2022;628:122298. https://doi.org/10.1016/j.ijpharm.2022.122298.

[160] Elkomy MH, Ali AA, Eid HM. Chitosan on the surface of nanoparticles for enhanced drug delivery: a comprehensive review. J Control Release. 2022; 351:923-940. https://doi.org/10.1016/j.jconrel.2022.10.005.

[161] Wu JR, Zhu ZJ, Liu W, et al. How nanoparticles open the paracellular route of biological barriers: mechanisms, applications, and prospects. ACS Nano. 2022; 16(10):15627-15652. https://doi.org/10.1021/acsnano.2c05317.

[162] Kalhapure RS, Palekar S, Patel K, et al. Nanocrystals for controlled delivery: state of the art and approved drug products. Expert Opin Drug Deliv. 2022; 19(10):1303-1316. https://doi.org/10.1080/17425247.2022.2110579.

[163] Pawar BM, Rahman SNR, Pawde DM, et al. Orally administered drug solubility-enhancing formulations: lesson learnt from optimum solubility-permeability balance. AAPS PharmSciTech. 2021; 22(2):63. https://doi.org/10.1208/s12249-021-01936-9.

[164] Li Y, Wang DQ, Lu S, et al. Pramipexole nanocrystals for transdermal permeation: characterization and its enhancement micro-mechanism. Eur J Pharm Sci. 2018; 124:80-88. https://doi.org/10.1016/j.ejps.2018.08.003.

[165] Ji Y, Li HR, Li JG, et al. Hair follicle-targeted delivery of azelaic acid micro/nanocrystals promote the treatment of acne vulgaris. Int J Nanomedicine. 2024; 19:5173-5191. https://doi.org/10.2147/IJN.S459788.

[166] Patel V, Sharma OP, Mehta T. Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery. Expert Opin Drug Deliv. 2018; 15(4):351-368. https://doi.org/10.1080/17425247.2018.1444025.

[167] Parveen N, Abourehab MAS, Thanikachalam PV, et al. Nanocrystals as an emerging nanocarrier for the management of dermatological diseases. Colloids Surf B Biointerfaces. 2023;225:113231. https://doi.org/10.1016/j.colsurfb.2023.113231.

[168] Parmar PK, Bansal AK. Novel nanocrystal-based formulations of apremilast for improved topical delivery. Drug Deliv Transl Res. 2021; 11(3):966-983. https://doi.org/10.1007/s13346-020-00809-1.

[169] Ahmed IS, Elnahas OS, Assar NH, et al. Nanocrystals of fusidic acid for dual enhancement of dermal delivery and antibacterial activity: in vitro, ex vivo and in vivo evaluation. Pharmaceutics. 2020; 12(3):199. https://doi.org/10.3390/pharmaceutics12030199.

[170] Sharma OP, Patel V, Mehta T. Nanocrystal for ocular drug delivery: hope or hype. Drug Deliv Transl Res. 2016; 6(4):399-413. https://doi.org/10.1007/s13346-016-0292-0.

[171] Baba K, Hashida N, Tujikawa M, et al. The generation of fluorometholone nanocrystal eye drops, their metabolization to dihydrofluorometholone and penetration into rabbit eyes. Int J Pharm. 2021;592:120067. https://doi.org/10.1016/j.ijpharm.2020.120067.

[172] Teng C, Li BB, Lin CS, et al. Targeted delivery of baicalein-p53 complex to smooth muscle cells reverses pulmonary hypertension. J Control Release. 2022; 341:591-604. https://doi.org/10.1016/j.jconrel.2021.12.006.

[173] Bolla G, Sarma B, Nangia AK. Crystal engineering of pharmaceutical cocrystals in the discovery and development of improved drugs. Chem Rev. 2022; 122(13):11514-11603. https://doi.org/10.1021/acs.chemrev.1c00987.

[174] Karagianni A, Malamatari M, Kachrimanis K. Pharmaceutical cocrystals: new solid phase modification approaches for the formulation of APIs. Pharmaceutics. 2018; 10(3):18. https://doi.org/10.3390/pharmaceutics10010018.

[175] Kale DP, Zode SS, Bansal AK. Challenges in translational development of pharmaceutical cocrystals. J Pharm Sci. 2017; 106(2):457-470. https://doi.org/10.1016/j.xphs.2016.10.021.

[176] Sible AM, Nawarskas JJ, Alajajian D, et al. Sacubitril/valsartan: a novel cardiovascular combination agent. Cardiol Rev. 2016; 24(1):41-47. https://doi.org/10.1097/CRD.0000000000000093.

[177] Langford R, Margarit C, Morte A, et al. Co-crystal of tramadol-celecoxib (CTC) for acute moderate-to-severe pain. Curr Med Res Opin. 2024; 40(3):455-468. https://doi: 10.1080/03007995.2023.2276118.

[178] Gascon N, Almansa C, Merlos M, et al. Co-crystal of tramadol-celecoxib: preclinical and clinical evaluation of a novel analgesic. Expert Opin Investig Drugs. 2019; 28(5):399-409. https://doi.org/10.1080/13543784.2019.1612557.

[179] Witika BA, Smith VJ, Walker RB. Top-down synthesis of a lamivudine-zidovudine nano co-crystal. Crystals. 2020;11:33. https://doi.org/10.3390/cryst11010033.

[180] Cheney ML, Weyna DR, Shan N, et al. Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. J Pharm Sci. 2011; 100(6):2172-2181. https://doi.org/10.1002/jps.22434.

[181] Žegarac M, Lekšić E, Šket P, et al. A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate. CrystEngComm. 2014; 16(1):32-35. https://doi.org/10.1039/C3CE42013B.

[182] Gagnière E, Mangin D, Puel F, et al. Formation of co-crystals: kinetic and thermodynamic aspects. J Cryst Growth. 2009; 311(9):2689-2695. https://doi.org/10.1016/j.jcrysgro.2009.02.040.

[183] Évora AOL, Castro RAE, Maria TMR, et al.Pyrazinamide-diflunisal: a new dual-drug co-crystal. Cryst Growth Des. 2011; 11(11):4780-4788. https://doi.org/10.1021/cg200288b.

[184] Báthori NB, Lemmerer A, Venter GA, et al. Pharmaceutical co-crystals with isonicotinamide—vitamin B3, clofibric acid, and diclofenac—and two isonicotinamide hydrates. Cryst Growth Des. 2011; 11(1):75-87. https://doi.org/10.1021/cg100670k.

[185] Lu J, Rohani S. Synthesis and preliminary characterization of sulfamethazine-theophylline co-crystal. J Pharm Sci. 2010; 99(9):4042-4047. https://doi.org/10.1002/jps.22142.

[186] Jiang LL, Huang Y, Zhang Q, et al. Preparation and solid-state characterization of dapsone drug-drug co-crystals. Cryst Growth Des. 2014; 14(9):4562-4573. https://doi.org/10.1021/cg500668a.

[187] Stanton MK, Bak A. Physicochemical properties of pharmaceutical co-crystals: a case study of ten AMG 517 co-crystals. Cryst Growth Des. 2008; 8(10):3856-3862. https://doi.org/10.1021/cg800173d.

[188] Buol X, Robeyns K, Garrido CC, et al. Improving nefiracetam dissolution and solubility behavior using a cocrystallization approach. Pharmaceutics. 2020; 12(7):653. https://doi.org/10.3390/pharmaceutics12070653.

[189] Erxleben A.Cocrystal applications in drug delivery. Pharmaceutics. 2020; 12(9):834. https://doi.org/10.3390/pharmaceutics12090834.

[190] Guo MS, Sun XJ, Chen JH, et al. Pharmaceutical cocrystals: a review of preparations, physicochemical properties and applications. Acta Pharm Sin B. 2021; 11(8):2537-2564. https://doi.org/10.1016/j.apsb.2021.03.030.

[191] Wang LY, Zhao MY, Bu FZ, et al. Cocrystallization of amantadine hydrochloride with resveratrol: the first drug-nutraceutical cocrystal displaying synergistic antiviral activity. Cryst Growth Des. 2021; 21(5):2763-2776. https://doi.org/10.1021/acs.cgd.0c01673.

[192] Wang SR, Heng WL, Wang XJ, et al. Coamorphization combined with complexation enhances dissolution of lurasidone hydrochloride and puerarin with synchronized release. Int J Pharm. 2020;588:119793. https://doi.org/10.1016/j.ijpharm.2020.119793.

[193] Kuminek G, Cao F, et al.De Oliveira Da Rocha AB, Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5. Adv Drug Deliv Rev. 2016; 101:143-166. https://doi.org/10.1016/j.addr.2016.04.022.

[194] Liu L, Li YG, Zhang M, et al. A drug-drug cocrystal of dihydromyricetin and pentoxifylline. J Pharm Sci. 2022; 111(1):82-87. https://doi.org/10.1016/j.xphs.2021.06.021.

[195] Wang J, Dai XL, Lu TB, et al. Temozolomide-hesperetin drug-drug cocrystal with optimized performance in stability, dissolution, and tabletability. Cryst Growth Des. 2021; 21:838-846. https://doi.org/10.1021/acs.cgd.0c01153.

[196] Shinozaki T, Ono M, Higashi K, et al. A novel drug-drug cocrystal of levofloxacin and metacetamol: reduced hygroscopicity and improved photostability of levofloxacin. J Pharm Sci. 2019; 108(7):2383-2390. https://doi.org/10.1016/j.xphs.2019.02.014.

[197] Mashhadi SMA, Batsanov AS, Sajjad SA, et al. Isoniazid-gentisic acid cocrystallization: solubility, stability, dissolution rate, antioxidant and flowability properties studies. J Mol Struct. 2021;1226(Part B):129388. https://doi.org/10.1016/j.molstruc.2020.129388.

[198] Xia YM, Lu Y, Qian S, et al. An efficient cocrystallization strategy for separation of dihydromyricetin from vine tea and enhanced its antibacterial activity for food preserving application. Food Chem. 2023;426:136525. https://doi.org/10.1016/j.foodchem.2023.136525.

[199] Shemchuk O, d’Agostino S, Fiore C, et al. Natural antimicrobials meet a synthetic antibiotic: carvacrol/thymol and ciprofloxacin cocrystals as a promising solid-state route to activity enhancement. Cryst Growth Des. 2020; 20(10):6796-6803. https://doi.org/10.1021/acs.cgd.0c00900.

[200] Wang XJ, Du SZ, Zhang R, et al.Drug-drug cocrystals: opportunities and challenges. Asian J Pharm Sci. 2021; 16(3):307-317. https://doi.org/10.1016/j.ajps.2020.06.004.

[201] Sun GX, Jin YD, Li SZ, et al. Virtual coformer screening by crystal structure predictions: crucial role of crystallinity in pharmaceutical cocrystallization. J Phys Chem Lett. 2020; 11(20):8832-8838. https://doi.org/10.1021/acs.jpclett.0c02371.

[202] Shaikh R, Singh R, Walker GM, et al. Pharmaceutical cocrystal drug products: an outlook on product development. Trends Pharmacol Sci. 2018; 39(12):1033-1048. https://doi.org/10.1016/j.tips.2018.10.006.

[203] Galek PTA, Fábián L, Motherwell WDS, et al. Knowledge-based model of hydrogen-bonding propensity in organic crystals. Acta Crystallogr B Struct Sci. 2007; 63(Pt 5):768-782. https://doi.org/10.1107/S0108768107030996.

[204] Singh M, Barua H, Jyothi VGSS, et al. Cocrystals by design: a rational coformer selection approach for tackling the API problems. Pharmaceutics. 2023; 15(4):1161. https://doi.org/10.3390/pharmaceutics15041161.

[205] Grosu IG, Filip X, Miclăuș MO, et al. Hydrogen-mediated noncovalent interactions in solids: what can NMR crystallography tell about?. Molecules. 2020; 25(16):3757. https://doi.org/10.3390/molecules25163757.

[206] Devogelaer J, Meekes H, Tinnemans P, et al. Co‐crystal prediction by artificial neural networks*. Angew Chem Int Ed Engl. 2020; 59(48):21711-21718. https://doi.org/10.1002/anie.202009467.

[207] Storer MC, Zator KJ, Reynolds DP, et al. An atomic surface site interaction point description of non-covalent interactions. Chem Sci. 2024; 15(1):160-170. https://doi.org/10.1039/D3SC05690B.

[208] Xie YF, Yuan PH, Heng TY, et al. Insight into the formation of cocrystal and salt of tenoxicam from the isomer and conformation. Pharmaceutics. 2022; 14(9):1968. https://doi.org/10.3390/pharmaceutics14091968.

[209] Musumeci D, Hunter CA, Prohens R, et al.Virtual cocrystal screening. Chem Sci. 2011; 2(5):883. https://doi.org/10.1039/c0sc00555j.

[210] Mohammad MA, Alhalaweh A, Velaga SP. Hansen solubility parameter as a tool to predict cocrystal formation. Int J Pharm. 2011; 407(1-2):63-71. https://doi.org/10.1016/j.ijpharm.2011.01.030.

[211] Banerjee M, Nimkar K, Naik S, et al. Unlocking the potential of drug-drug cocrystals-a comprehensive review. J Control Release. 2022; 348:456-469. https://doi.org/10.1016/j.jconrel.2022.06.003.

[212] Rodríguez-Hornedo N. Cocrystals: molecular design of pharmaceutical materials. Mol Pharmaceut. 2007; 4(3):299-300. https://doi.org/10.1021/mp070042v.

[213] Heng WL, Song YT, Luo MQ, et al. Mechanistic insights into the crystallization of coamorphous drug systems. J Control Release. 2023; 354:489-502. https://doi.org/10.1016/j.jconrel.2023.01.019.

[214] Khansary MA, Shirazian S, Walker G. Molecular engineering of cocrystallization process in holt melt extrusion based on kinetics of elementary molecular processes. Int J Pharm. 2021;601:120495. https://doi.org/10.1016/j.ijpharm.2021.120495.

[215] Grecu T, Hunter CA, Gardiner EJ, et al. Validation of a computational cocrystal prediction tool: comparison of virtual and experimental cocrystal screening results. Cryst Growth Des. 2014; 14(1):165-171. https://doi.org/10.1021/cg401339v.

[216] Aakeröy CB, Wijethunga TK, Desper J. Molecular electrostatic potential dependent selectivity of hydrogen bonding. New J Chem. 2015; 39:822-828. https://doi.org/10.1039/C4NJ01324G.

[217] Reddy LS, Bethune SJ, Kampf JW, et al. Cocrystals and salts of gabapentin: pH dependent cocrystal stability and solubility. Cryst Growth Des. 2009; 9(1):378-385. https://doi.org/10.1021/cg800587y.

[218] Cruz-Cabeza AJ. Acid-base crystalline complexes and the pKa rule. CrystEngComm. 2012; 14(20):6362. https://doi.org/10.1039/c2ce26055g.

[219] Childs SL, Stahly GP, Park A. The salt-cocrystal continuum: the influence of crystal structure on ionization state. Mol Pharmaceut. 2007; 4(3):323-338. https://doi.org/10.1021/mp0601345.

[220] Bashimam M, El-Zein H. Pharmaceutical cocrystal of antibiotic drugs: a comprehensive review. Heliyon. 2022; 8 (12):e11872. https://doi.org/10.1016/j.heliyon.2022.e11872.

[221] Ren J, Zhang WJ, Zhang TH, et al. A simple and efficient strategy for constructing nitrogen-rich isomeric salts and cocrystal through pKa calculation. J Mol Struct. 2021;1223:128955. https://doi.org/10.1016/j.molstruc.2020.128955.

[222] Salem A, Nagy S, Pál S, et al. Reliability of the Hansen solubility parameters as co-crystal formation prediction tool. Int J Pharm. 2019; 558:319-327. https://doi.org/10.1016/j.ijpharm.2019.01.007.

[223] Greenhalgh DJ, Williams AC, Timmins P, et al. Solubility parameters as predictors of miscibility in solid dispersions. J Pharm Sci. 1999; 88(11):1182-1190. https://doi.org/10.1021/js9900856.

[224] Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry. 2018. https://www.fda.gov/media/81824/download.

[225] Yeh KL, Lee HL, Lee T. Crystallization of form II paracetamol with the assistance of carboxylic acids toward batch and continuous processes. Pharmaceutics. 2022; 14(5):1099. https://doi.org/10.3390/pharmaceutics14051099.

[226] Bo YH, Fang JY, Zhang ZM, et al. Terahertz and Raman spectroscopic investigation of monohydrate cocrystal of antitubercular isoniazid with protocatechuic acid. Pharmaceutics. 2021; 13(8):1303. https://doi.org/10.3390/pharmaceutics13081303.

[227] Xia MY, Jiang YH, Cheng YX, et al. Rucaparib cocrystal: improved solubility and bioavailability over camsylate. Int J Pharm. 2023;631:122461. https://doi.org/10.1016/j.ijpharm.2022.122461.

[228] Witika BA, Smith VJ, Walker RB. A comparative sudy of the effect of different stabilizers on the critical quality attributes of self-assembling nano co-crystals. Pharmaceutics. 2020; 12(2):182. https://doi.org/10.3390/pharmaceutics12020182.

[229] Mohammady M, Hadidi M, Ghetmiri SI, et al. Design of ultra-fine carvedilol nanococrystals: development of a safe and stable injectable formulation. Eur J Pharm Biopharm. 2021; 168:139-151. https://doi.org/10.1016/j.ejpb.2021.08.015.

[230] Nandi S, Padrela L, Tajber L, et al. Development of long-acting injectable suspensions by continuous antisolvent crystallization: an integrated bottom-up process. Int J Pharm. 2023;648:123550. https://doi.org/10.1016/j.ijpharm.2023.123550.

[231] Gajda M, Nartowski KP, Pluta J, et al. Continuous, one-step synthesis of pharmaceutical cocrystals via hot melt extrusion from neat to matrix-assisted processing-State of the art. Int J Pharm. 2019; 558:426-440. https://doi.org/10.1016/j.ijpharm.2019.01.016.

[232] Zhang DJ, Xu SJ, Du SC, et al.Progress of pharmaceutical continuous crystallization. Engineering. 2017; 3(3):354-364. https://doi.org/10.1016/J.ENG.2017.03.023.

[233] Ma YM, Wu SG, Macaringue EGJ, et al. Recent progress in continuous crystallization of pharmaceutical products: precise preparation and control. Org Process Res Dev. 2020; 24(10):1785-1801. https://doi.org/10.1021/acs.oprd.9b00362.

[234] Karimi-Jafari M, Ziaee A, Iqbal J, et al. Impact of polymeric excipient on cocrystal formation via hot-melt extrusion and subsequent downstream processing. Int J Pharm. 2019; 566:745-755. https://doi.org/10.1016/j.ijpharm.2019.06.031.

[235] Wong SN, Weng JW, Ip I, et al. Rational development of a carrier-free dry powder inhalation formulation for respiratory viral Infections via quality by design: a drug-drug cocrystal of favipiravir and theophylline. Pharmaceutics. 2022; 14(2):300. https://doi.org/10.3390/pharmaceutics14020300.

[236] Cole KP. What elements contribute to a high-quality continuous processing submission for OPR&D?. Org Process Res Dev. 2020; 24(10):1781-1784. https://doi.org/10.1021/acs.oprd.0c00020.

[237] Gutmann B, Cantillo D, Kappe CO. Continuous‐flow technology—a tool for the safe manufacturing of active pharmaceutical Ingredients. Angew Chem Int Ed Engl. 2015; 54(23):6688-6728. https://doi.org/10.1002/anie.201409318.

[238] Thipparaboina R, Kumar D, Chavan RB, et al. Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov Today. 2016; 21(3):481-490. https://doi.org/10.1016/j.drudis.2016.02.001.

[239] Meng FF, Wang JP, Ping QN, et al. Camouflaging nanoparticles for ratiometric delivery of therapeutic combinations. Nano Lett. 2019; 19(3):1479-1487. https://doi.org/10.1021/acs.nanolett.8b04017.

[240] Zhang XB, Sun BJ, Zuo SY, et al. Self-assembly of a pure photosensitizer as a versatile theragnostic nanoplatform for imaging-guided antitumor photothermal therapy. ACS Appl Mater Interfaces. 2018; 10(36):30155-30162. https://doi.org/10.1021/acsami.8b10421.

[241] Zhang XB, Xiong JC, Wang KY, et al. Erythrocyte membrane-camouflaged carrier-free nanoassembly of FRET photosensitizer pairs with high therapeutic efficiency and high security for programmed cancer synergistic phototherapy. Bioact Mater. 2021; 6(8):2291-2302. https://doi.org/10.1016/j.bioactmat.2021.01.004.

[242] Fu SW, Li GT, Zang WL, et al. Pure drug nano-assemblies: a facile carrier-free nanoplatform for efficient cancer therapy. Acta Pharm Sin B. 2022; 12(1):92-106. https://doi.org/10.1016/j.apsb.2021.08.012.

[243] Zhang J, Li S, An FF, et al. Self-carried curcumin nanoparticles for in vitro and in vivo cancer therapy with real-time monitoring of drug release. Nanoscale. 2015; 7(32):13503-13510. https://doi.org/10.1039/C5NR03259H.

[244] Zhao Q, Feng MY, Jin S, et al. 10,11-Dehydrocurvularin attenuates inflammation by suppressing NLRP3 inflammasome activation. Chin J Nat Med. 2023; 21(3):163-171. https://doi.org/10.1016/S1875-5364(23)60418-2.

[245] Zhao DJ, Tian C, Cheng M, et al. Carrier-free quercetin nanomedicine blocks NLRP3 deubiquitination and TXNIP recruitment for Parkinson’s disease therapy. Chem Eng J. 2023;464:142697. https://doi.org/10.1016/j.cej.2023.142697.

[246] Mandl LA. Osteoarthritis year in review 2018: clinical. Osteoarthr Cartilage. 2019; 27(3):359-364. https://doi.org/10.1016/j.joca.2018.11.001.

[247] Peng XJ, Li XT, Xie B, et al.Gout therapeutics and drug delivery. J Control Release. 2023; 362:728-754. https://doi.org/10.1016/j.jconrel.2023.09.011.

[248] Dai WW, Jin P, Li XY, et al. A carrier-free nano-drug assembled via π-π stacking interaction for the treatment of osteoarthritis. Biomed Pharmacother. 2023;164:114881. https://doi.org/10.1016/j.biopha.2023.114881.

[249] Lu JH, Wang ZJ, Cai DS, et al. Carrier-free binary self-assembled nanomedicines originated from traditional herb medicine with multifunction to accelerate MRSA-infected wound healing by antibacterial, anti-inflammation and promoting angiogenesis. Int J Nanomed. 2023; 18:4885-4906. https://doi.org/10.2147/IJN.S422944.

[250] Wen Y, Zhang W, Gong NQ, et al. Carrier-free, self-assembled pure drug nanorods composed of 10-hydroxycamptothecin and chlorin e6 for combinatorial chemo-photodynamic antitumor therapy in vivo. Nanoscale. 2017; 9(38):14347-14356. https://doi.org/10.1039/C7NR03129G.

[251] Shamay Y, Shah J, Işık M, et al. Quantitative self-assembly prediction yields targeted nanomedicines. Nature Mater. 2018; 17(4):361-368. https://doi.org/10.1038/s41563-017-0007-z.

[252] Zhang JF, Li YN, An FF, et al. Preparation and size control of sub-100 nm pure nanodrugs. Nano Lett. 2015; 15(1):313-318. https://doi.org/10.1021/nl503598u.

[253] Li GT, Sun BJ, Li YQ, et al. Small‐molecule prodrug nanoassemblies: an emerging nanoplatform for anticancer drug delivery. Small. 2021; 17(52):2101460. https://doi.org/10.1002/smll.202101460.

[254] Sis MJ, Ye Z, La Costa K, et al. Energy landscapes of supramolecular peptide-drug conjugates directed by linker selection and drug topology. ACS Nano. 2022; 16(6):9546-9558. https://doi.org/10.1021/acsnano.2c02804.

[255] Pei Q, Hu XL, Liu S, et al. Paclitaxel dimers assembling nanomedicines for treatment of cervix carcinoma. J Control Release. 2017; 254:23-33. https://doi.org/10.1016/j.jconrel.2017.03.391.

[256] Wang ZL, Yang LJ. Natural-product-based, carrier-free, noncovalent nanoparticles for tumor chemo-photodynamic combination therapy. Pharmacol Res. 2024;203:107150. https://doi: 10.1016/j.phrs.2024.107150.

[257] Zhang JF, Nie WD, Chen R, e al. Green mass production of pure nanodrugs via an ice-template-assisted strategy. Nano Lett. 2019; 19(2):658-665. https://doi.org/10.1021/acs.nanolett.8b03043.

[258] Fan LL, Zhang BC, Xu AX, et al. Carrier-free, pure nanodrug formed by the self-assembly of an anticancer drug for cancer immune therapy. Mol Pharm. 2018; 15(6):2466-2478. https://doi.org/10.1021/acs.molpharmaceut.8b00444.

[259] Li YW, Zhang W, Shi NY, et al. Self-assembly and self-delivery of the pure nanodrug dihydroartemisinin for tumor therapy and mechanism analysis. Biomater Sci. 2023; 11(7):2478-2485. https://doi.org/10.1039/D2BM01949C.

[260] Karaosmanoglu S, Zhang Y, Zhou W, et al. Synthesis of carrier-free paclitaxel-curcumin nanoparticles: the role of curcuminoids. Bioengineering. 2022; 9(12):815. https://doi.org/10.3390/bioengineering9120815.

[261] Sun MD, Zhang Y, He Y, et al. Green synthesis of carrier-free curcumin nanodrugs for light-activated breast cancer photodynamic therapy. Colloids Surf B Biointerfaces. 2019; 180:313-318. https://doi.org/10.1016/j.colsurfb.2019.04.061.

[262] Tian YY, Tang G, Gao YH, et al. Carrier-free small molecular self-assembly based on berberine and curcumin incorporated in submicron particles for improving antimicrobial activity. ACS Appl Mater Interfaces. 2022; 14(8):10055-10067. https://doi: 10.1021/acsami.1c22900.

[263] Huang XM, Wang PL, Li T, et al. Self-assemblies based on traditional medicine berberine and cinnamic acid for adhesion-induced inhibition multidrug-resistant Staphylococcus aureus. ACS Appl Mater Interfaces. 2020; 12:227-237. https://doi.org/10.1021/acsami.9b17722.

[264] Si JM, Han H, Chen BT, et al. Natural product-based drug delivery for treating fibroinflammatory diseases. Chin J Nat Med. 2024: 24(1):1-12. https://doi.org/10.1016/S1875-5364(24)60648-5.

[265] Wu PK, Luo XP, Wu H, et al. Efficient and targeted chemo-gene delivery with self-assembled fluoro-nanoparticles for liver fibrosis therapy and recurrence. Biomaterials. 2020;261:120311. https://doi.org/10.1016/j.biomaterials.2020.120311.

[266] Zhong QY, Zeng JQ, Jia XB, et al. Self-assembled aggregated structures of natural products for oral drug delivery. Int J Nanomed. 2024; 19:5931-5949. https://doi.org/10.2147/IJN.S467354.

[267] Lucarini V, Melaiu O, D’Amico S, et al. Combined mitoxantrone and anti-TGFβ treatment with PD-1 blockade enhances antitumor immunity by remodelling the tumor immune landscape in neuroblastoma. J Exp Clin Cancer Res. 2022; 41(1):326. https://doi.org/10.1186/s13046-022-02525-9.

[268] Abu Samaan TM, Samec M, Liskova A, et al. Paclitaxel’s mechanistic and clinical effects on breast cancer. Biomolecules. 2019; 9(12);789. https://doi.org/10.3390/biom9120789.

[269] Zhou MJ, Zhang XJ, Yang YL, et al. Carrier-free functionalized multidrug nanorods for synergistic cancer therapy. Biomaterials. 2013; 34(35):8960-8967. https://doi.org/10.1016/j.biomaterials.2013.07.080.

[270] Zhao LY, Liu YM, Chang R, et al. Supramolecular photothermal nanomaterials as an emerging paradigm toward precision cancer therapy. Adv Funct Materials. 2019;29:1806877. https://doi.org/10.1002/adfm.201806877.

[271] Huang L, Asghar S, Zhu T, et al. Advances in chlorin-based photodynamic therapy with nanoparticle delivery system for cancer treatment. Expert Opin Drug Deliv. 2021; 18(10):1473-1500. https://doi.org/10.1080/17425247.2021.1950685.

[272] Long KQ, Han H, Kang WR, et al. One-photon red light-triggered disassembly of small-molecule nanoparticles for drug delivery. J Nanobiotechnol. 2021; 19(1):357. https://doi.org/10.1186/s12951-021-01103-z.

[273] Shen LJ, Zhou TJ, Fan YT, et al. Recent progress in tumor photodynamic immunotherapy. Chin Chem Lett. 2020; 31(7):1709-1716. https://doi.org/10.1016/j.cclet.2020.02.007.

[274] Zhao C, Liu WW, Sun WL, et al. Activatable self-assembled organic nanotheranostics: aspartyl aminopeptidase triggered NIR fluorescence imaging-guided photothermal/photodynamic synergistic therapy. Anal Chim Acta. 2022;1231:340198. https://doi.org/10.1016/j.aca.2022.340198.

[275] Stapleton S, Dunne M, Milosevic M, et al. Radiation and heat improve the delivery and efficacy of nanotherapeutics by modulating intratumoral fluid dynamics. ACS Nano. 2018; 12(8):7583-7600. https://doi.org/10.1021/acsnano.7b06301.

[276] Wang Y, Yang PF, Zhao XR, et al. Multifunctional cargo-free nanomedicine for cancer therapy. Int J Mol Sci. 2018; 19(10):2963. https://doi.org/10.3390/ijms19102963.

[277] Zhang RY, Xing RR, Jiao TF, et al. Carrier-free, chemophotodynamic dual nanodrugs via self-assembly for synergistic antitumor therapy. ACS Appl Mater Interfaces. 2016; 8(21):13262-13269. https://doi.org/10.1021/acsami.6b02416.

[278] Li XY, Deng FA, Zheng RR, et al. Carrier free photodynamic synergists for oxidative damage amplified tumor therapy. Small. 2021; 17(40):2102470. https://doi.org/10.1002/smll.202102470.

[279] Zhang DY, Liang YQ, Wang MC, et al. Self‐assembled carrier‐free nanodrugs for starvation therapy‐amplified photodynamic therapy of cancer. Adv Healthc Mater. 2023; 12(20):2203177. https://doi.org/10.1002/adhm.202203177.

[280] Kang XY, Zhang Y, Song JW, et al. A photo-triggered self-accelerated nanoplatform for multifunctional image-guided combination cancer immunotherapy. Nat Commun. 2023; 14(1):5216. https://doi.org/10.1038/s41467-023-40996-2.

[281] Fei JB, Dai LR, Gao FP, et al. Assembled vitamin B2 nanocrystals with optical waveguiding and photosensitizing properties for potential biomedical application. Angew Chem Int Ed Engl. 2019; 58(22):7254-7258. https://doi.org/10.1002/anie.201900124.

[282] Zheng RR, Liu YB, Yu BX, et al. Carrier free nanomedicine for synergistic cancer therapy by initiating apoptosis and paraptosis. J Colloid Interface Sci. 2022; 622:298-308. https://doi.org/10.1016/j.jcis.2022.04.090.

[283] Zhao LP, Zheng RR, Chen HQ, et al. Self-delivery nanomedicine for O₂ -economized photodynamic tumor therapy. Nano Lett. 2020; 20(3):2062-2071. https://doi.org/10.1021/acs.nanolett.0c00047.

[284] Li XY, Kong RJ, Li YM, et al. Carrier-free nanomedicine for enhanced photodynamic tumor therapy through glutathione S-transferase inhibition. Chem Commun. 2022; 58(24):3917-3920. https://doi.org/10.1039/D2CC00235C.

[285] Guo Y, Jiang K, Shen ZC, et al. A small molecule nanodrug by self-assembly of dual anticancer drugs and photosensitizer for synergistic near-infrared cancer theranostics. ACS Appl Mater Interfaces. 2017; 9(50):43508-43519. https://doi.org/10.1021/acsami.7b14755.

[286] De Grand AM, Frangioni JV. An operational near-infrared fluorescence imaging system prototype for large animal surgery. Technol Cancer Res Treat. 2023; 2(6):553-562. https://doi.org/10.1177/153303460300200607.

[287] Tynga IM, Abrahamse H. Nano-mediated photodynamic therapy for cancer: enhancement of cancer specificity and therapeutic effects. Nanomaterials. 2018; 8(11):923. https://doi.org/10.3390/nano8110923.

[288] Zhang LL, Lu JJ. Combination strategies for first-line treatment of patients with unresectable hepatocellular carcinoma: prospect of natural products. Chin J Nat Med. 2024; 22(1):1-3. https://doi.org/10.1016/S1875-5364(24)60574-1.

[289] Xiao QQ, Li XT, Liu C, et al. Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator. Acta Pharm Sin B. 2023; 13(8):3503-3517. https://doi.org/10.1016/j.apsb.2022.07.012.

[290] Cai SX, Chen ZY, Wang YJ, et al. Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced chemo-immunotherapy. Theranostics. 2021; 11(4):1970-1981. https://doi.org/10.7150/thno.45777.

[291] Shen JH, Ye XQ, Hou H, et al. Clinical evidence for the prognostic impact of metformin in cancer patients treated with immune checkpoint inhibitors. Int Immunopharmacol. 2024;134:112243. https://doi.org/10.1016/j.intimp.2024.112243.

[292] Yuan ZN, Zheng YQ, Wang BH. Prodrugs of hydrogen sulfide and related sulfur species: recent development. Chin J Nat Med. 2020; 18(4):296-307. https://doi.org/10.1016/S1875-5364(20)30037-6.

[293] Ling X, Tu JS, Wang JQ, et al. Glutathione-responsive prodrug nanoparticles for effective drug delivery and cancer therapy. ACS Nano. 2019; 13(1):357-370. https://doi.org/10.1021/acsnano.8b06400.

[294] Vong LB, Sato Y, Chonpathompikunlert P, et al. Self-assembled polydopamine nanoparticles improve treatment in Parkinson’s disease model mice and suppress dopamine-induced dyskinesia. Acta Biomater. 2020; 109:220-228. https://doi.org/10.1016/j.actbio.2020.03.021.

[295] Xu HE, Lu XW, Li J, et al. Superior antitumor effect of extremely high drug loading self-assembled paclitaxel nanofibers. Int J Pharm. 2017; 526 (1-2):217-224. https://doi.org/10.1016/j.ijpharm.2017.04.081.

[296] Jing FB, Guo Q, Xu W, et al. Docetaxel prodrug self-assembled nanosystem: synthesis, formulation and cytotoxicity. Bioorg Med Chem Lett. 2018; 28(4):826-830. https://doi.org/10.1016/j.bmcl.2017.07.041.

[297] Couvreur P, Stella B, Reddy LH, et al.Squalenoyl nanomedicines as potential therapeutics. Nano Lett. 2006; 6(11):2544-2548. https://doi.org/10.1021/nl061942q.

[298] Yin SP, Huai J, Chen X, et al. Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid. Acta Biomater. 2015; 26:274-285. https://doi.org/10.1016/j.actbio.2015.08.029.

[299] Riber CF, Smith AAA, Zelikin AN. Self‐immolative linkers literally bridge disulfide chemistry and the realm of thiol‐free drugs. Adv Healthc Mater. 2015; 4(12):1887-1890. https://doi.org/10.1002/adhm.201500344.

[300] Zhang HB, Zhang YB, Chen YL, et al. Glutathione-responsive self-delivery nanoparticles assembled by curcumin dimer for enhanced intracellular drug delivery. Int J Pharm. 2018; 549(1-2):230-238. https://doi.org/10.1016/j.ijpharm.2018.07.061.

[301] Zheng YF, Qin C, Li F, et al. Self-assembled thioether-bridged paclitaxel-dihydroartemisinin prodrug for amplified antitumor efficacy-based cancer ferroptotic-chemotherapy. Biomater Sci. 2023; 11(9):3321-3334. https://doi.org/10.1039/D2BM02032G.

[302] Han XF, Chen JL, Jiang MJ, et al. Paclitaxel-paclitaxel prodrug nanoassembly as a versatile nanoplatform for combinational cancer therapy. ACS Appl Mater Interfaces. 2016; 8(49):33506-33513. https://doi.org/10.1021/acsami.6b13057.

[303] Zhou ZH, Piao Y, Hao LQ, et al. Acidity-responsive shell-sheddable camptothecin-based nanofibers for carrier-free cancer drug delivery. Nanoscale. 2019; 11(34):15907-15916. https://doi.org/10.1039/C9NR03872H.

[304] Ao MT, Yu F, Li YX, et al. Carrier-free nanoparticles of camptothecin prodrug for chemo-photothermal therapy: the making, in vitro and in vivo testing. J Nanobiotechnol. 2021; 19(1):350. https://doi.org/10.1186/s12951-021-01093-y.

[305] Yu N, Liu T, Zhang X, et al. Dually enzyme- and acid-triggered self-immolative ketal glycoside nanoparticles for effective cancer prodrug monotherapy. Nano Lett. 2020; 20(7):5465-5472. https://doi.org/10.1021/acs.nanolett.0c01973.

[306] Wang KK, Yuan AH, Yu JQ, et al. One-step self-assembling method to prepare dual-functional transferrin nanoparticles for antitumor drug delivery. J Pharm Sci. 2016; 105(3):1269-1276. https://doi.org/10.1016/j.xphs.2015.12.007.

[307] Wu C, Liu J, Tang X, et al. An enzyme-assisted self-delivery system of lonidamine-peptide conjugates for selectively killing cancer cells. Chem Commun. 2019; 55(98):14852-14855. https://doi.org/10.1039/C9CC06204A.

[308] Liu J, Wu C, Dai GR, et al. Molecular self-assembly of a tyroservatide-derived octapeptide and hydroxycamptothecin for enhanced therapeutic efficacy. Nanoscale. 2021; 13(9):5094-5102. https://doi.org/10.1039/D0NR08741F.

[309] Zhou JQ, Li YY, Huang WL, et al. Source and exploration of the peptides used to construct peptide-drug conjugates. Eur J Med Chem. 2021;224:113712. https://doi.org/10.1016/j.ejmech.2021.113712.

[310] Shim MK, Park J, Yoon HY, et al. Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy. J Control Release. 2019; 294:376-389. https://doi.org/10.1016/j.jconrel.2018.11.032.

[311] Chen Y, Liang GL. Enzymatic self-assembly of nanostructures for theranostics. Theranostics. 2012; 2(2):139-147. https://doi.org/10.7150/thno.3696.

[312] Liu LH, Zhang XZ.Carrier-free nanomedicines for cancer treatment. Prog Mater Sci. 2022;125:100919. https://doi.org/10.1016/j.pmatsci.2021.100919.

[313] Miao QQ, Bai XY, Shen YY, et al. Intracellular self-assembly of nanoparticles for enhancing cell uptake. Chem Commun. 2012; 48(78):9738. https://doi.org/10.1039/c2cc34899c.

[314] Yao QX, Huang ZT, Liu DD, et al. Enzyme‐instructed supramolecular self‐assembly with anticancer activity. Adv Mater. 2019; 31(45):e1804814. https://doi.org/10.1002/adma.201804814.

[315] Liang CH, Yan XR, Zhang RS, et al. Enhanced cellular uptake and nuclear accumulation of drug-peptide nanomedicines prepared by enzyme-instructed self-assembly. J Control Release. 2020; 317:109-117. https://doi.org/10.1016/j.jconrel.2019.11.028.

[316] Gupta A, Andresen JL, Manan RS, et al. Nucleic acid delivery for therapeutic applications. Adv Drug Deliv Rev. 2021;178:113834. https://doi.org/10.1016/j.addr.2021.113834.

[317] Tan XY, Jia F, Wang P, et al.Nucleic acid-based drug delivery strategies. J Control Release. 2020; 323:240-252. https://doi.org/10.1016/j.jconrel.2020.03.040.

[318] Zhang WT, Jiang YX, He YL, et al.Lipid carriers for mRNA delivery. Acta Pharm Sin B. 2023; 13(10):4105-4126. https://doi.org/10.1016/j.apsb.2022.11.026.

[319] Yang YX, Ning HJ, Xia TP, et al. Electrostatic attractive self‐delivery of siRNA and light‐induced self‐escape for synergistic gene therapy. Adv Mater. 2023; 35(30):e2301409. https://doi.org/10.1002/adma.202301409.

[320] Bazak R, Houri M, El Achy S, et al. Cancer active targeting by nanoparticles: a comprehensive review of literature. J Cancer Res Clin Oncol. 2015; 141(5):769-784. https://doi.org/10.1007/s00432-014-1767-3.

[321] Lou HT, Cao XT. Antibody variable region engineering for improving cancer immunotherapy. Cancer Commun. 2022; 42(9):804-827. https://doi.org/10.1002/cac2.12330.

[322] Ministro J, Manuel AM, Goncalves J. Therapeutic antibody engineering and selection strategies. Adv Biochem Eng Biotechnol. 2020; 171:55-86. https://doi.org/10.1007/10_2019_116.

[323] Jovčevska I, Muyldermans S.The therapeutic potential of nanobodies. BioDrugs. 2020; 34(1):11-26. https://doi.org/10.1007/s40259-019-00392-z.

[324] Jin BK, Odongo S, Radwanska M, et al. Nanobodies: a review of generation, diagnostics and therapeutics. Int J Mol Sci. 2023;24:5994. https://doi.org/10.3390/ijms24065994.

[325] Richards DA. Exploring alternative antibody scaffolds: antibody fragments and antibody mimics for targeted drug delivery. Drug Discov Today Technol. 2018; 30:35-46. https://doi.org/10.1016/j.ddtec.2018.10.005.

[326] Tereshko V, Uysal S, Koide A, et al. Toward chaperone‐assisted crystallography: protein engineering enhancement of crystal packing and X‐ray phasing capabilities of a camelid single‐domain antibody (V_HH) scaffold. Protein Sci. 2008; 17(7):1175-1187. https://doi.org/10.1110/ps.034892.108.

[327] Muyldermans S.Applications of nanobodies. Annu Rev Anim Biosci. 2021; 9:401-421. https://doi.org/10.1146/annurev-animal-021419-083831.

[328] Verhaar ER, Woodham AW, Ploegh HL. Nanobodies in cancer. Semin Immunol. 2021;52:101425. https://doi.org/10.1016/j.smim.2020.101425.

[329] Salvador JP, Vilaplana L, Marco MP. Nanobody: outstanding features for diagnostic and therapeutic applications. Anal Bioanal Chem. 2019; 411(9):1703-1713. https://doi.org/10.1007/s00216-019-01633-4.

[330] Kunz S, Durandy M, Seguin L, et al. NANOBODY^® molecule, a giga medical tool in nanodimensions. Int J Mol Sci. 2023; 24(17):13229. https://doi.org/10.3390/ijms241713229.

[331] Kunz P, Zinner K, Mücke N, et al. The structural basis of nanobody unfolding reversibility and thermoresistance. Sci Rep. 2018; 8(1):7934. https://doi.org/10.1038/s41598-018-26338-z.

[332] Govaert J, Pellis M, Deschacht N, et al. Dual beneficial effect of interloop disulfide bond for single domain antibody fragments. J Biol Chem. 2012; 287(3):1970-1979. https://doi.org/10.1074/jbc.M111.242818.

[333] Lecocq Q, De Vlaeminck Y, Hanssens H, et al. Theranostics in immuno-oncology using nanobody derivatives. Theranostics. 2019; 9(25):7772-7791. https://doi.org/10.7150/thno.34941.

[334] De Genst E, Silence K, Decanniere K, et al. Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies. Proc Natl Acad Sci USA. 2006; 103(12):4586-4591. https://doi.org/10.1073/pnas.0505379103.

[335] Sun SY, Ding ZQ, Yang XM, et al. Nanobody: a small antibody with big implications for tumor therapeutic strategy. Int J Nanomed. 2021; 16:2337-2356. https://doi.org/10.2147/IJN.S297631.

[336] Smolarek D, Bertrand O, Czerwinski M. Variable fragments of heavy chain antibodies (VHHs): a new magic bullet molecule of medicine?. Postepy Hig Med Dosw. 2012; 66:348-358. https://doi.org/10.5604/17322693.1000334.

[337] Sang Z, Xiang Y, Bahar I, et al. Llamanade: an open-source computational pipeline for robust nanobody humanization. Structure. 2022; 30(3):418-429.e3. https://doi.org/10.1016/j.str.2021.11.006.

[338] Chakravarty R, Goel S, Cai WB. Nanobody: the “magic bullet” for molecular imaging?. Theranostics. 2014; 4(4): 386-398. https://doi.org/10.7150/thno.8006.

[339] Temple WC, Nix MA, Naik A, et al. Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies. J Immunother Cancer. 2023; 11(11):e006985. https://doi.org/10.1136/jitc-2023-006985.

[340] Debie P, Lafont C, Defrise M, et al. Size and affinity kinetics of nanobodies influence targeting and penetration of solid tumours. J Control Release. 2020; 317:34-42. https://doi.org/10.1016/j.jconrel.2019.11.014.

[341] Keyaerts M, Xavier C, Heemskerk J, et al. Phase I study of ⁶⁸Ga-HER2-nanobody for PET/CT assessment of HER2 expression in breast carcinoma. J Nucl Med. 2016; 57(1):27-33. https://doi.org/10.2967/jnumed.115.162024.

[342] Muyldermans S. A guide to: generation and design of nanobodies. FEBS J. 2021; 288(7):2084-2102. https://doi.org/10.1111/febs.15515.

[343] Kim JYJ, Sang Z, Xiang YF, et al. Nanobodies: robust miniprotein binders in biomedicine. Adv Drug Deliv Rev. 2023;195:114726. https://doi.org/10.1016/j.addr.2023.114726.

[344] Liu MM, Li L, Jin D, et al. Nanobody—a versatile tool for cancer diagnosis and therapeutics. Wiley Interdiscip Nanomed Nanobiotechnol. 2021; 13(4):e1697. https://doi.org/10.1002/wnan.1697.

[345] Panikar SS, Banu N, Haramati J, et al. Nanobodies as efficient drug-carriers: progress and trends in chemotherapy. J Control Release. 2021; 334:389-412. https://doi.org/10.1016/j.jconrel.2021.05.004.

[346] Nguyen VK, Hamers R, Wyns L, et al. Camel heavy-chain antibodies: diverse germline VHH and specific mechanisms enlarge the antigen-binding repertoire. EMBO J. 2000; 19(5):921-930. https://doi.org/10.1093/emboj/19.5.921.

[347] Akiba H, Tamura H, Kiyoshi M, et al. Structural and thermodynamic basis for the recognition of the substrate-binding cleft on hen egg lysozyme by a single-domain antibody. Sci Rep. 2019; 9(1):15481. https://doi.org/10.1038/s41598-019-50722-y.

[348] Stijlemans B, Conrath K, Cortez-Retamozo V, et al. Efficient targeting of conserved cryptic epitopes of infectious agents by single domain antibodies. J Biol Chem. 2004; 279(2):1256-1261. https://doi.org/10.1074/jbc.M307341200.

[349] Hempelmann A, Hartleb L, Van Straaten M, et al. Nanobody-mediated macromolecular crowding induces membrane fission and remodeling in the African trypanosome. Cell Rep. 2021; 37(5):109923. https://doi.org/10.1016/j.celrep.2021.109923.

[350] Arias JL, Unciti-Broceta JD, Maceira J, et al. Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis. J Control Release. 2015; 197:190-198. https://doi.org/10.1016/j.jconrel.2014.11.002.

[351] Abbady AQ, Al-Daoude A, Al-Mariri A, et al. Chaperonin GroEL a Brucella immunodominant antigen identified using Nanobody and MALDI-TOF-MS technologies. Vet Immunol Immunopathol. 2012; 146 (3-4):254-263. https://doi.org/10.1016/j.vetimm.2012.01.015.

[352] Deng HK, Zhou J, Gong BB, et al.Screening and identification of a human domain antibody against Brucella abortus VirB5. Acta Trop.20019;197:105026. https://doi.org/10.1016/j.actatropica.2019.05.017.

[353] Rudolph M, Carsten A, Kulnik S, et al. Live imaging of Yersinia translocon formation and immune recognition in host cells. PLoS Pathog. 2022; 18(5):e1010251. https://doi.org/10.1371/journal.ppat.1010251.

[354] Deckers N, Saerens D, Kanobana K, et al. Nanobodies, a promising tool for species-specific diagnosis of Taenia solium cysticercosis. Int J Parasitol. 2009; 39(5):625-633. https://doi.org/10.1016/j.ijpara.2008.10.012.

[355] Sun MX, Sun Y, Yang YB, et al. Multivalent nanobody-based sandwich enzyme-linked immunosorbent assay for sensitive detection of porcine reproductive and respiratory syndrome virus. Int J Biol Macromol. 2024; 258(Pt 2):128896. https://doi.org/10.1016/j.ijbiomac.2023.128896.

[356] Wang YD, Xianyu YL. Nanobody and nanozyme‐enabled immunoassays with enhanced specificity and sensitivity. Small Methods. 2022; 6(4):e2101576. https://doi.org/10.1002/smtd.202101576.

[357] Koide S.Engineering of recombinant crystallization chaperones. Curr Opin Struct Biol. 2009; 19(4):449-457. https://doi.org/10.1016/j.sbi.2009.04.008.

[358] Korotkov KV, Pardon E, Steyaert J, et al. Crystal structure of the N-terminal domain of the secretin GspD from ETEC determined with the assistance of a nanobody. Structure. 2009; 17(2):255-265. https://doi.org/10.1016/j.str.2008.11.011.

[359] Hunte C, Michel H. Crystallisation of membrane proteins mediated by antibody fragments. Curr Opin Struct Biol. 2002; 12(4):503-508. https://doi.org/10.1016/S0959-440X(02)00354-8.

[360] Götzke H, Kilisch M, Martínez-Carranza M, et al. The ALFA-tag is a highly versatile tool for nanobody-based bioscience applications. Nat Commun. 2019; 10(1):4403. https://doi.org/10.1038/s41467-019-12301-7.

[361] Ma JB, Xu XL, Fu CJ, et al. CDH17 nanobodies facilitate rapid imaging of gastric cancer and efficient delivery of immunotoxin. Biomater Res. 2022; 26(1):64. https://doi.org/10.1186/s40824-022-00312-3.

[362] Altunay B, Morgenroth A, Beheshti M, et al. HER2-directed antibodies, affibodies and nanobodies as drug-delivery vehicles in breast cancer with a specific focus on radioimmunotherapy and radioimmunoimaging. Eur J Nucl Med Mol Imaging. 2021; 48:1371-1389. https://doi.org/10.1007/s00259-020-05094-1.

[363] Zeven K, De Groof TWM, Ceuppens H, et al. Development and evaluation of nanobody tracers for noninvasive nuclear imaging of the immune-checkpoint TIGIT. Front Immunol. 2023;14:1268900. https://doi.org/10.3389/fimmu.2023.1268900.

[364] Yu XL, Long YR, Chen BF, et al. PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way. J Immunother Cancer. 2022; 10(10):e004590. https://doi.org/10.1136/jitc-2022-004590.

[365] Xu CL, Zhu M, Wang Q, et al. TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer. J Nanobiotechnol. 2023; 21(1):410. https://doi.org/10.1186/s12951-023-02183-9.

[366] Danquah W, Meyer-Schwesinger C, Rissiek B, et al. Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation. Sci Transl Med. 2016; 8(366):366ra162. https://doi.org/10.1126/scitranslmed.aaf8463.

[367] Zettl I, Ivanova T, Zghaebi M, et al. Generation of high affinity ICAM-1-specific nanobodies and evaluation of their suitability for allergy treatment. Front Immunol. 2022;13:1022418. https://doi.org/10.3389/fimmu.2022.1022418.

[368] Koenig PA, Das H, Liu H, et al. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science. 2021; 371(6530):eabe6230. https://doi.org/10.1126/science.abe6230.

[369] Zhao LY, Meng FL, Li YJ, et al. Multivalent nanobody conjugate with rigid, reactive oxygen species scavenging Scaffold for multi‐target therapy of Alzheimer’s disease. Adv Mater. 2023; 35(17):e2210879. https://doi.org/10.1002/adma.202210879.

[370] Alirahimi E, Kazemi-Lomedasht F, Shahbazzadeh D, et al. Nanobodies as novel therapeutic agents in envenomation. Biochim Biophys Acta Gen Subj. 2018; 1862(12):2955-2965. https://doi.org/10.1016/j.bbagen.2018.08.019.

[371] Schumacher D, Helma J, Schneider AFL, et al. Nanobodies: chemical functionalization strategies and intracellular applications. Angew Chem Int Ed Engl. 2018; 57(9):2314-2333. https://doi.org/10.1002/anie.201708459.

[372] Ward AB, Szewczyk P, Grimard V, et al. Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc Natl Acad Sci USA. 2013; 110(33):13386-13391. https://doi.org/10.1073/pnas.1309275110.

[373] Esparza TJ, Martin NP, Anderson GP, et al. High affinity nanobodies block SARS-CoV-2 spike receptor binding domain interaction with human angiotensin converting enzyme. Sci Rep. 2020; 10(1):22370. https://doi.org/10.1038/s41598-020-79036-0.

[374] Darvish M, Ebrahimi SA, Shahbazzadeh D, et al. Camelid antivenom development and potential in vivo neutralization of Hottentotta saulcyi scorpion venom. Toxicon. 2016; 113:70-75. https://doi.org/10.1016/j.toxicon.2016.01.063.

[375] May C, Sapra P, Gerber HP. Advances in bispecific biotherapeutics for the treatment of cancer. Biochem Pharmacol. 2012; 84(9):1105-1112. https://doi.org/10.1016/j.bcp.2012.07.011.

[376] Heukers R, Van Bergen En Henegouwen PMP, Oliveira S. Nanobody-photosensitizer conjugates for targeted photodynamic therapy. Nanomedicine. 2014; 10(7):1441-1451. https://doi.org/10.1016/j.nano.2013.12.007.

[377] Maza JC, García Almedina DM, Boike LE, et al.Tyrosinase-mediated synthesis of nanobody-cell conjugates. ACS Cent Sci. 2022; 8(7):955-962. https://doi.org/10.1021/acscentsci.1c01265.

[378] Shim H. Bispecific antibodies and antibody-drug conjugates for cancer therapy: technological considerations. Biomolecules. 2020; 10(3):360. https://doi.org/10.3390/biom10030360.

[379] Bargh JD, Isidro-Llobet A, Parker JS, et al.Cleavable linkers in antibody-drug conjugates. Chem Soc Rev. 2019; 48(16):4361-4374. https://doi.org/10.1039/C8CS00676H.

[380] Passaro A, Jänne PA, Peters S. Antibody-drug conjugates in lung cancer: recent advances and implementing strategies. J Clin Oncol. 2023; 41(21):3747-3761. https://doi.org/10.1200/JCO.23.00013.

[381] Jedema I, Barge RMY, et al.Van Der Velden VHJ, Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity. Leukemia. 2004; 18(2):316-325. https://doi.org/10.1038/sj.leu.2403205.

[382] Butler DC, Joshi SN, Genst ED, et al. Bifunctional anti-non-amyloid component α-synuclein nanobodies are protective in situ. PLoS One.. 2016; 11(11):e0165964. https://doi.org/10.1371/journal.pone.0165964.

[383] Dumontet C, Reichert JM, Senter PD, et al. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov. 2023; 22(8):641-661. https://doi.org/10.1038/s41573-023-00709-2.

[384] Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008; 41:98-107. https://doi.org/10.1021/ar700108g.

[385] Khan T, Lyons NJ, Gough M, et al. CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy. Theranostics. 2022; 12(16):6915-6930. https://doi.org/10.7150/thno.78171.

[386] Khan T, Kryza T, Lyons NJ, et al. The CDCP1 signaling hub: a target for cancer detection and therapeutic intervention. Cancer Res. 2021; 81(9):2259-2269. https://doi.org/10.1158/0008-5472.CAN-20-2978.

[387] Hafeez U, Parakh S, Gan HK, et al.Antibody-drug conjugates for cancer therapy. Molecules. 2020; 25(20):4764. https://doi.org/10.3390/molecules25204764.

[388] Caculitan NG, Chuh JDC, Ma Y, et al. Cathepsin B is dispensable for cellular processing of cathepsin B-cleavable antibody-drug conjugates. Cancer Res. 2017; 77(24):7027-7037. https://doi.org/10.1158/0008-5472.CAN-17-2391.

[389] Antrás JF, Genta S, Vijenthira A, et al. Antibody-drug conjugates: in search of partners of choice. Trends Cancer. 2023; 9(4):339-354. https://doi.org/10.1016/j.trecan.2023.01.003.

[390] Shekarian T, Valsesia-Wittmann S, Brody J, et al. Pattern recognition receptors: immune targets to enhance cancer immunotherapy. Ann Oncol. 2017; 28(8):1756-1766. https://doi.org/10.1093/annonc/mdx179.

[391] Richardson JJ, Caruso F. Nanomedicine toward 2040. Nano Lett. 2020; 20(3):1481-1482. https://doi.org/10.1021/acs.nanolett.0c00620.

[392] Bakker L, Aarts J, de Groot CU, et al. Economic evaluations of big data analytics for clinical decision-making: a scoping review. J Am Med Inform Assoc. 2020; 27(9):1466-1475. https://doi.org/10.1093/jamia/ocaa102.

[393] Mayo CS, Matuszak MM, Schipper MJ, et al. Big data in designing clinical trials: opportunities and challenges. Front Oncol. 2017;7:187. https://doi.org/10.3389/fonc.2017.00187.

[394] Brothers JF, Ung M, Escalante-Chong R, et al. Integrity, standards, and QC-related issues with big data in pre-clinical drug discovery. Biochem Pharmacol. 2018; 152:84-93. https://doi.org/10.1016/j.bcp.2018.03.014.

[395] Hay M, Thomas DW, Craighead JL, et al. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014; 32(1):40-51. https://doi.org/10.1038/nbt.2786.

[396] Pammolli F, Magazzini L, Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov. 2011; 10(6):428-438. https://doi.org/10.1038/nrd3405.

[397] DiMasi JA, Feldman L, Seckler A, et al. Trends in risks associated with new drug development: success rates for investigational drugs. Clin Pharmacol Ther. 2010; 87(3):272-277. https://doi.org/10.1038/clpt.2009.295.

[398] Farjadian F, Ghasemi A, Gohari O, et al. Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportunities. Nanomedicine. 2019; 14(1):93-126. https://doi.org/10.2217/nnm-2018-0120.

[399] Venditto VJ, Szoka FC. Cancer nanomedicines: so many papers and so few drugs!. Adv Drug Deliv Rev. 2013; 65(1):80-88. https://doi.org/10.1016/j.addr.2012.09.038.

[400] Greish K, Mathur A, Bakhiet M, et al. Nanomedicine: is it lost in translation?. Ther Deliv. 2018; 9(4):269-285. https://doi.org/10.4155/tde-2017-0118.

[401] Farid SS. Process economics of industrial monoclonal antibody manufacture. J Chromatogr B Analyt Technol Biomed Life Sci. 2007; 848(1):8-18. https://doi.org/10.1016/j.jchromb.2006.07.037.

[402] Muller RH, Keck CM. Challenges and solutions for the delivery of biotech drugs--a review of drug nanocrystal technology and lipid nanoparticles. J Biotechnol. 2004; 113(1-3):151-170. https://doi.org/10.1016/j.jbiotec.2004.06.007.

[403] Wilson AW, Neumann PJ. The cost-effectiveness of biopharmaceuticals: a look at the evidence. MAbs. 2012; 4(2):281-288. https://doi.org/10.4161/mabs.4.2.18812.

[404] Havel H, Finch G, Strode P, et al. Nanomedicines: from bench to bedside and beyond. AAPS J. 2016; 18(6):1373-1378. https://doi.org/10.1208/s12248-016-9961-7.

[405] Liu BQ, He HQ, Luo HY, et al. Artificial intelligence and big data facilitated targeted drug discovery. Stroke Vasc Neurol. 2019; 4(4):206-213. https://doi.org/10.1136/svn-2019-000290.

[406] Wu LP, Wang DY, Li ZB.Grand challenges in nanomedicine. Mater Sci Eng C Mater Biol Appl. 2020;106:110302. https://doi.org/10.1016/j.msec.2019.110302.

[407] Sinha B, Müller RH, Möschwitzer JP. Bottom-up approaches for preparing drug nanocrystals: Formulations and factors affecting particle size. Int J Pharm. 2013; 453(1):126-141. https://doi.org/10.1016/j.ijpharm.2013.01.019.

[408] Müller RH, Gohla S, Keck CM. State of the art of nanocrystals--special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm. 2011; 78(1):1-9. https://doi.org/10.1016/j.ejpb.2011.01.007.

[409] Leong HS, Butler KS, Brinker CJ, et al. Publisher correction: on the issue of transparency and reproducibility in nanomedicine. Nat Nanotechnol. 2019; 14(8):811-811. https://doi.org/10.1038/s41565-019-0523-x.

[410] Paliwal R, Babu RJ, Palakurthi S. Nanomedicine scale-up technologies: feasibilities and challenges. AAPS PharmSciTech. 2014; 15(6):1527-1534. https://doi.org/10.1208/s12249-014-0177-9.

[411] Carvalho PM, Felício MR, Santos NC, et al. Application of light scattering techniques to nanoparticle characterization and development. Front Chem. 2018;6:237. https://doi.org/10.3389/fchem.2018.00237.

[412] Lin PC, Lin S, Wang PC, et al. Techniques for physicochemical characterization of nanomaterials. Biotechnol Adv. 2014; 32(4):711-726. https://doi.org/10.1016/j.biotechadv.2013.11.006.

[413] Donahue ND, Acar H, Wilhelm S. Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. Adv Drug Deliv Rev. 2019; 143:68-96. https://doi.org/10.1016/j.addr.2019.04.008.

[414] Schütz CA, Juillerat-Jeanneret L, Mueller H, et al. Therapeutic nanoparticles in clinics and under clinical evaluation. Nanomedicine. 2013; 8(3):449-467. https://doi.org/10.2217/nnm.13.8.

[415] Kuschnerus I, Giri K, Ruan J, et al. On the growth of the soft and hard protein corona of mesoporous silica particles with varying morphology. J Colloid Interface Sci. 2022; 612:467-478. https://doi.org/10.1016/j.jcis.2021.12.161.

[416] Boucetta H, Zhang L, Sosnik A, et al. Pulmonary arterial hypertension nanotherapeutics: new pharmacological targets and drug delivery strategies. J Control Release. 2024; 365:236-258. https://doi.org/10.1016/j.jconrel.2023.11.012.

[417] Soisuwan S, Teeranachaideekul V, Wongrakpanich A, et al. Impact of uncharged and charged stabilizers on in vitro drug performances of clarithromycin nanocrystals. Eur J Pharm Biopharm. 2019; 137:68-76. https://doi.org/10.1016/j.ejpb.2019.02.004.

[418] Gutmann DAP, Ward A, Urbatsch IL, et al.Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1. Trends Biochem Sci. 2010; 35(1):36-42. https://doi.org/10.1016/j.tibs.2009.07.009.

[419] Luo ZM, Lu LW, Xu WX, et al. In vivo self-assembled drug nanocrystals for metastatic breast cancer all-stage targeted therapy. J Control Release. 2022; 346:32-42. https://doi.org/10.1016/j.jconrel.2022.03.058.

[420] Ferrari M, Philibert M, Sanhai W. Nanomedicine and society. Clin Pharmacol Ther. 2009; 85(5):466-467. https://doi.org/10.1038/clpt.2008.276.

[421] Grizzi F, Chiriva-Internati M. Cancer: looking for simplicity and finding complexity. Cancer Cell Int. 2006;6:4. https://doi.org/10.1186/1475-2867-6-4.

[422] Katsios C, Roukos DH. Individual genomes and personalized medicine: life diversity and complexity. Per Med. 2010; 7(4):347-350. https://doi.org/10.2217/pme.10.30.

[423] Stratton MR, Campbell PJ, Futreal PA.The cancer genome. Nature. 2009; 458(7239):719-724. https://doi.org/10.1038/nature07943.

[424] Bashyam MD, Animireddy S, Bala P, et al. The Yin and Yang of cancer genes. Gene. 2019; 704:121-133. https://doi.org/10.1016/j.gene.2019.04.025.

[425] Gottesman MM, Lavi O, Hall MD, et al. Toward a better understanding of the complexity of cancer drug resistance. Annu Rev Pharmacol Toxicol. 2016; 56:85-102. https://doi.org/10.1146/annurev-pharmtox-010715-103111.

[426] Li XT, Peng XJ, Zoulikha M, et al. Multifunctional nanoparticle-mediated combining therapy for human diseases. Sig Transduct Target Ther. 2024; 9(1):1. https://doi.org/10.1038/s41392-023-01668-1.

[427] Aleksakhina SN, Kashyap A, Imyanitov EN. Mechanisms of acquired tumor drug resistance. Biochim Biophys Acta Rev Cancer. 2019; 1872(2): 188310. https://doi.org/10.1016/j.bbcan.2019.188310.

[428] Swartz MA, Iida N, Roberts EW, et al. Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res. 2012; 72(10):2473-2480. https://doi.org/10.1158/0008-5472.CAN-12-0122.

[429] Nakamura Y, Mochida A, Choyke PL, et al. Nanodrug delivery: is the enhanced permeability and retention effect sufficient for curing cancer?. Bioconjugate Chem. 2016; 27(10):2225-2238. https://doi.org/10.1021/acs.bioconjchem.6b00437.

[430] Zi YX, Yang KY, He JH, et al. Strategies to enhance drug delivery to solid tumors by harnessing the EPR effects and alternative targeting mechanisms. Adv Drug Deliv Rev. 2022;188:114449. https://doi.org/10.1016/j.addr.2022.114449.

[431] Shi JJ, Kantoff PW, Wooster R, et al. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017; 17(1):20-37. https://doi.org/10.1038/nrc.2016.108.

[432] Gao HL, Pang ZQ, He W. Editorial of special issue on tumor microenvironment and drug delivery. Acta Pharm Sin B. 2020; 10(11):2016-2017. https://doi.org/10.1016/j.apsb.2020.11.017.

[433] Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012; 125(Pt 23):5591-5596. https://doi.org/10.1242/jcs.116392.

[434] Hui LL, Chen Y. Tumor microenvironment: sanctuary of the devil. Cancer Lett. 2015; 368(1):7-13. https://doi.org/10.1016/j.canlet.2015.07.039.

[435] Hare JI, Lammers T, Ashford MB, et al. Challenges and strategies in anti-cancer nanomedicine development: an industry perspective. Adv Drug Deliv Rev. 2017: 108:25-38. https://doi.org/10.1016/j.addr.2016.04.025.

[436] Cohen SM. Human relevance of animal carcinogenicity studies. Regul Toxicol Pharmacol. 1995; 21(1):75-80. https://doi.org/10.1006/rtph.1995.1012.

[437] Toxicity tests in animals: extrapolating to human risks. Environ Health Perspect. 1993; 101(5):396-401. https://doi.org/10.1289/ehp.101-1519837.

[438] Allon I, Yehudah AB, Dekel R, et al. Ethical issues in nanomedicine: tempest in a teapot?. Med Health Care and Philos. 2017; 20(1):3-11. https://doi.org/10.1007/s11019-016-9720-7.

[439] Henderson GE, Easter MM, Zimmer C, et al. Therapeutic misconception in early phase gene transfer trials. Soc Sci Med. 2006; 62(1):239-253. https://doi.org/10.1016/j.socscimed.2005.05.022.

[440] Glenn LM, Boyce JS. Regenerative nanomedicine: ethical, legal, and social issues. Methods Mol Biol. 2012; 811:303-16. https://doi.org/10.1007/978-1-61779-388-2_19.

[441] Resnik DB. Developing drugs for the developing world: an economic, legal, moral, and political dilemma. Dev World Bioeth. 2001; 1(1):11-32. https://doi.org/10.1111/1471-8847.00004.

[442] Sigfridsson K, Forssén S, Holländer P, et al. A formulation comparison, using a solution and different nanosuspensions of a poorly soluble compound. Eur J Pharm Biopharm. 2007; 67(2):540-547. https://doi.org/10.1016/j.ejpb.2007.02.008.

[443] Xue N, Jia YT, Li CW, et al. Characterizations and assays of α-glucosidase inhibition activity on gallic acid cocrystals: can the cocrystals be defined as a new chemical entity during binding with the α-glucosidase?. Molecules. 2020;25:1163. https://doi.org/10.3390/molecules25051163.

[444] Wang ZP, Xie YF, Yu MC, et al. Recent advances on the biological study of pharmaceutical cocrystals. AAPS PharmSciTech. 2022; 23(8):303. https://doi.org/10.1208/s12249-022-02451-1.