Nano-TPD for precision protein degradation via endogenous or exogenous triggered release

Abstract

Targeted protein degradation (TPD) technology offers a revolutionary approach for precise intervention against “undruggable” targets by exploiting intracellular pathways such as the ubiquitin-proteasome system and the autophagy-lysosome system. However, its clinical translation faces significant challenges, including limited delivery efficiency, poor tissue specificity, and off-target toxicity. The integration of nanotechnology with TPD not only overcomes the physicochemical limitations of traditional TPD molecules [e.g., Proteolysis-Targeting Chimeras (PROTACs), Autophagosome-Tethering Compounds (ATTECs), Lysosome-Targeting Chimeras (LYTACs), molecular glues] through the design of functionalized carriers but also equips these systems with spatiotemporal precision activation via diverse regulation of “initiation conditions”. This review systematically traces the developmental trajectory and fundamental mechanisms of TPD technology, explores the delivery characteristics and principles of functional modification in nanocarriers, and comprehensively discusses the design strategies, mechanisms, and recent advances of nanotyped TPD systems categorized by their initiation conditions: endogenous microenvironment-responsive [pH, enzyme, reactive oxygen species (ROS)/glutathione (GSH)], exogenous stimulus-initiated (light, magnetic, ultrasound, bioorthogonal reaction), and multi-conditionally co-initiated systems (endogenous-endogenous and endogenous-exogenous signal synergy). Furthermore, this review highlights key challenges in the field, such as carrier biocompatibility, modulation of degradation efficiency, and in vivo fate tracking, while outlining critical directions for clinical translation, including personalized customization, intelligent logic gating, and multimodal characterization. By providing a systematic theoretical framework and practical insights, this review aims to promote cross-disciplinary integration and foster innovative drug development at the intersection of nanotechnology and TPD.

Keywords

Targeted protein degradation / nanocarriers / endogenous response / exogenous stimuli / ubiquitin-proteasome system / precision delivery

References

[1] Cromm P. M.,Crews C. M.. Targeted protein degradation: from chemical biology to drug discovery Cell Chem. Biol. 2017 24 1181 90 PMC5610075

[2] Farley K.,Bhattacharya S.,Cleland J.,Chandran P.,Wu J.. The targeted protein degradation landscape Nat. Rev. Drug Discov. 2025 24 164 5

[3] Zhang G.,Yan S.,Liu Y.,Du Z.,Min Q.,Qin S.. PROTACs coupled with oligonucleotides to tackle the undruggable Bioanalysis 2025 17 261 76 PMC11864318

[4] Zhang C.,Liu Y.,Li G..et al. Targeting the undruggables-the power of protein degraders Sci. Bull. 2024 69 1776 97

[5] Yan S.,Zhang G.,Luo W..et al. PROTAC technology: From drug development to probe technology for target deconvolution Eur. J. Med. Chem. 2024 276 116725

[6] Yoon H.,Rutter J. C.,Li Y. D.,Ebert B. L.. Induced protein degradation for therapeutics: past, present, and future J. Clin. Invest. 2024 134 e175265 10760958

[7] Kelm J. M.,Pandey D. S.,Malin E..et al. PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy Mol. Cancer 2023 22 62

[8] Qin S.,Xiao X.. Key advances and application prospects of PROTAC technologies in the next 5 years Future Med. Chem. 2025 17 987 9 PMC12091913

[9] Kim J.,Byun I.,Kim D. Y.,Joh H.,Kim H. J.,Lee M. J.. Targeted protein degradation directly engaging lysosomes or proteasomes Chem. Soc. Rev. 2024 53 3253 72

[10] Zhou Z.,Liang J.,Cheng B..et al. Targeted degradation technologies utilizing autophagy Int. J. Mol. Sci. 2025 26 6576 PMC12295361

[11] Xie H.,Zhang C.. Potential of the nanoplatform and PROTAC interface to achieve targeted protein degradation through the ubiquitin-proteasome system Eur. J. Med. Chem. 2024 267 116168

[12] Gonçalves A. L.,Cunha P. M.,da Silva Lima A.,Dos Santos J. C.,Segato F.. Production of recombinant lytic polysaccharide monooxygenases and evaluation effect of its addition into Aspergillus fumigatus var. niveus cocktail for sugarcane bagasse saccharification Biochim. Biophys. Acta. Proteins Proteom. 2023 1871 140919

[13] Price E.,Weinheimer M.,Rivkin A..et al. Beyond rule of five and PROTACs in modern drug discovery: polarity reducers, chameleonicity, and the evolving physicochemical landscape J. Med. Chem. 2024 67 5683 98

[14] Pike A.,Williamson B.,Harlfinger S.,Martin S.,McGinnity D. F.. Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective Drug Discov. Today 2020 25 1793 800

[15] Shi J.,Wang L.,Zeng X..et al. Precision-engineered PROTACs minimize off-tissue effects in cancer therapy Front. Mol. Biosci. 2024 11 1505255 PMC11621628

[16] Syahputra E. W.,Lee H.,Cho H.,Park H. J.,Park K. S.,Hwang D.. PROTAC delivery strategies for overcoming physicochemical properties and physiological barriers in targeted protein degradation Pharmaceutics 2025 17 501 PMC12030311

[17] Toriki E. S.,Papatzimas J. W.,Nishikawa K..et al. Rational chemical design of molecular glue degraders ACS Cent. Sci. 2023 9 915 26

[18] Stanton C.,Nutsch K.,Bollong M. J.. Stressing out with electrophiles Nat. Chem. Biol. 2025 21 612 3

[19] Zhang X. J.,Chen S.,Huang K. X.,Le W. D.. Why should autophagic flux be assessed? Acta Pharmacol. Sin. 2013 34 595 9 PMC4002868

[20] Wu Y.,Lin B.,Lu Y..et al. Aptamer-LYTACs for targeted degradation of extracellular and membrane proteins Angew. Chem. Int. Ed. 2023 62 e202218106

[21] Mikitiuk M.,Barczyński J.,Bielski P..et al. IGF2 peptide-based LYTACs for targeted degradation of extracellular and transmembrane proteins Molecules 2023 28 7519 PMC10673611

[22] Mu X.,Mu C.,Wang M.,Meng C.,Liu H.,Lu H.. Nanotechnology advances proteolysis targeting chimeras (PROTACs): transition from basic research to clinical application Int. J. Nanomedicine 2025 20 12177 98 12513389

[23] Peer D.,Karp J. M.,Hong S.,Farokhzad O. C.,Margalit R.,Langer R.. Nanocarriers as an emerging platform for cancer therapy Nat. Nanotechnol. 2007 2 751 60

[24] Mitchell M. J.,Billingsley M. M.,Haley R. M.,Wechsler M. E.,Peppas N. A.,Langer R.. Engineering precision nanoparticles for drug delivery Nat. Rev. Drug Discov. 2021 20 101 24 PMC7717100

[25] Wilhelm S.,Tavares A. J.,Dai Q..et al. Analysis of nanoparticle delivery to tumours Nat. Rev. Mater. 2016 1 16014

[26] Rodriguez‐abetxuko A.,Romero‐ben E.,Ontoria A..et al. Engineered metal‐loaded biohybrids to promote the attachment and electron‐shuttling between enzymes and carbon electrodes Adv. Funct. Mater. 2024 34 2400479

[27] Zhong J.,Zhao R.,Wang Y.,Su Y. X.,Lan X.. Nano-PROTACs: state of the art and perspectives Nanoscale 2024 16 4378 91

[28] Kim J.,Cho H.,Lim D. K.,Joo M. K.,Kim K.. Perspectives for improving the tumor targeting of nanomedicine via the EPR Effect in clinical tumors Int. J. Mol. Sci. 2023 24 10082 PMC10298311

[29] Sun J.,Gu M.,Peng L..et al. A Self-assembled nano-molecular glue (Nano-mGlu) enables GSH/H₂O₂-triggered targeted protein degradation in cancer therapy J. Am. Chem. Soc. 2025 147 372 83

[30] Xu M.,Chen J.,Wang S..et al. Autophagy-activating nanoautophagosome-tethering compounds for targeted protein degradation specifically in tumor cells ACS Macro Lett. 2025 14 250 7

[31] Xing Y.,Li J.,Wang L..et al. A bifunctional lysosome-targeting chimera nanoplatform for tumor-selective protein degradation and enhanced cancer immunotherapy Adv. Mater. 2025 37 e2417942

[32] Zhong G.,Chang X.,Xie W.,Zhou X.. Targeted protein degradation: advances in drug discovery and clinical practice Signal Transduct. Target. Ther. 2024 9 308 PMC11539257

[33] Kashyap D.,Milne T.,Booth M.. DNA-programmable protein degradation: dynamic control of PROTAC activity via DNA hybridization and strand displacement ChemRxiv. 2025

[34] Torres J.,Valenzuela Oses J. K.,Rabasco-Álvarez A. M.,González-Rodríguez M. L.,García M. C.. Innovations in cancer therapy: endogenous stimuli-responsive liposomes as advanced nanocarriers Pharmaceutics 2025 17 245 PMC11858840

[35] Thomas R. G.,Surendran S. P.,Jeong Y. Y.. Tumor microenvironment-stimuli responsive nanoparticles for anticancer therapy Front. Mol. Biosci. 2020 7 610533 PMC7775573

[36] Whitesides G. M.,Grzybowski B.. Self-assembly at all scales Science 2002 295 2418 21

[37] Sahay G.,Alakhova D. Y.,Kabanov A. V.. Endocytosis of nanomedicines J. Control. Release 2010 145 182 95 PMC2902597

[38] Li L. M.,Xie Y. P.,Qin Y. R..et al. Tumor microenvironment‐responsive drug self‐delivery systems to treat cancer and overcome MDR Rare Metals 2024 44 1 33

[39] Liu Y.,Si L.,Jiang Y..et al. Design of pH-responsive nanomaterials based on the tumor microenvironment Int. J. Nanomedicine 2025 20 705 21 11752822

[40] Pei D.,Buyanova M.. Overcoming endosomal entrapment in drug delivery Bioconjugate Chem. 2019 30 273 83 PMC6501178

[41] Varkouhi A. K.,Scholte M.,Storm G.,Haisma H. J.. Endosomal escape pathways for delivery of biologicals J. Control. Release 2011 151 220 8

[42] Huh K. M.,Kang H. C.,Lee Y. J.,Bae Y. H.. pH-sensitive polymers for drug delivery Macromol. Res. 2012 20 224 33

[43] Akinc A.,Thomas M.,Klibanov A. M.,Langer R.. Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis J. Gene Med. 2005 7 657 63

[44] Shin Y.,Husni P.,Kang K..et al. Recent advances in pH- or/and photo-responsive nanovehicles Pharmaceutics 2021 13 725 PMC8157172

[45] Kanamala M.,Wilson W. R.,Yang M.,Palmer B. D.,Wu Z.. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: a review Biomaterials 2016 85 152 67

[46] Huang L.,Sun X.,Zuo Q..et al. A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines Mater. Today. Bio 2025 31 101523 PMC11810845

[47] Blanco E.,Shen H.,Ferrari M.. Principles of nanoparticle design for overcoming biological barriers to drug delivery Nat. Biotechnol. 2015 33 941 51 PMC4978509

[48] Du J.,Lane L. A.,Nie S.. Stimuli-responsive nanoparticles for targeting the tumor microenvironment J. Control. Release 2015 219 205 14 PMC4656063

[49] Cui M.,Zhang D.,Zheng X..et al. Intelligent modular DNA lysosome-targeting chimera nanodevice for precision tumor therapy J. Am. Chem. Soc. 2024 146 29609 20

[50] Min H.,Sun M. C.,Hu K..et al. Ionizable nano-PROTAC overcomes endosomal entrapment for enhanced LRG1 degradation and tumor suppression Angew. Chem. Int. Ed. 2026 65 e20235

[51] Kessenbrock K.,Plaks V.,Werb Z.. Matrix metalloproteinases: regulators of the tumor microenvironment Cell 2010 141 52 67 PMC2862057

[52] Wang H. X.,Yang X. Z.,Sun C. Y.,Mao C. Q.,Zhu Y. H.,Wang J.. Matrix metalloproteinase 2-responsive micelle for siRNA delivery Biomaterials 2014 35 7622 34

[53] Pang Q.,Xu Z.,Sun T..et al. Strategic chemical synthesis and application of nanocarriers responsive to the tumor microenvironment Nano Today 2024 58 102421

[54] Kim D.,Yang G.,Lim C..et al. Cancer specific CAIX-targeting supramolecular lysosome-targeting chimeras (Supra-LYTAC) for targeted protein degradation Adv. Sci. 2025 12 e2503134

[55] Kapalatiya H.,Madav Y.,Tambe V. S.,Wairkar S.. Enzyme-responsive smart nanocarriers for targeted chemotherapy: an overview Drug Deliv. Transl. Res. 2022 12 1293 305

[56] Tong F.,Wang Y.,Xu Y..et al. MMP-2-triggered, mitochondria-targeted PROTAC-PDT therapy of breast cancer and brain metastases inhibition Nat. Commun. 2024 15 10382 PMC11607387

[57] Song C.,Jiao Z.,Hou Z..et al. Selective protein of interest degradation through the split-and-mix liposome proteolysis targeting chimera approach J. Am. Chem. Soc. 2023 145 21860 70

[58] Yang F.,Luo Q.,Wang Y..et al. Targeted biomolecule regulation platform: a split-and-mix PROTAC approach J. Am. Chem. Soc. 2023 145 7879 87

[59] Zhou Z.,Ni K.,Deng H.,Chen X.. Dancing with reactive oxygen species generation and elimination in nanotheranostics for disease treatment Adv. Drug Delivery Rev. 2020 158 73 90

[60] Yang B.,Chen Y.,Shi J.. Reactive oxygen species (ROS)-based nanomedicine Chem. Rev. 2019 119 4881 985

[61] Zhao C.,Chen J.,Zhong R.,Chen D. S.,Shi J.,Song J.. Oxidative-species-selective materials for diagnostic and therapeutic applications Angew. Chem. Int. Ed. 2021 60 9804 27

[62] Ye H.,Zhou Y.,Liu X..et al. Recent advances on reactive oxygen species-responsive delivery and diagnosis system Biomacromolecules 2019 20 2441 63

[63] Lee M. H.,Yang Z.,Lim C. W..et al. Disulfide-cleavage-triggered chemosensors and their biological applications Chem. Rev. 2013 113 5071 109

[64] Lv H.,Zhen C.,Liu J.,Yang P.,Hu L.,Shang P.. Unraveling the potential role of glutathione in multiple forms of cell death in cancer therapy Oxid. Med. Cell. Longev. 2019 2019 3150145 PMC6590529

[65] Liu H.,Ren C.,Sun R..et al. Reactive oxygen species-responsive Pre-PROTAC for tumor-specific protein degradation Chem. Commun. 2022 58 10072 5

[66] Bi T.,Liang P.,Zhao Q..et al. Targeted degradation of bromodomain-containing protein 4 enabled by reactive oxygen species-activatable NanoPROTACs as an efficient strategy to reverse liver fibrosis in chronic liver injury J. Med. Chem. 2025 68 6328 38

[67] Yao Q.,Wu Z.,Li J..et al. Reactive oxygen species-instructed supramolecular assemblies enable bioorthogonally activatable protein degradation for pancreatic cancer J. Am. Chem. Soc. 2025 147 18208 18

[68] Liu H. J.,Chen W.,Wu G..et al. Glutathione-scavenging nanoparticle-mediated PROTACs delivery for targeted protein degradation and amplified antitumor effects Adv. Sci. 2023 10 e2207439

[69] Lin J. Y.,Wu Y.,Liang X. H..et al. A self-assembling LYTAC mediates CTGF degradation and remodels inflammatory tumor microenvironment for triple-negative breast cancer therapy Adv. Sci. 2025 12 e2500311

[70] Saravanakumar G.,Kim J.,Kim W. J.. Reactive-oxygen-species-responsive drug delivery systems: promises and challenges Adv. Sci. 2017 4 1600124

[71] Liou G. Y.,Storz P.. Reactive oxygen species in cancer Free Radical Res. 2010 44 479 96 PMC3880197

[72] Xie F.,Wang M.,Chen Q..et al. Endogenous stimuli-responsive nanoparticles for cancer therapy: from bench to bedside Pharmacol. Res. 2022 186 106522

[73] Gao J.,Yang L.,Lei S..et al. Stimuli-activatable PROTACs for precise protein degradation and cancer therapy Sci. Bull. 2023 68 1069 85

[74] Zhu M.,Wang X.,Zhou Y..et al. Breast tumor‐targeted drug delivery via polymer nanocarriers: endogenous and exogenous strategies J. Appl. Polym. Sci. 2023 140 e54227

[75] Wang N.,Cong W.,Zhu Y..et al. Spatiotemporally controlled protein degradation via NIR-activatable PROTAC platform Sci. China Chem. 2025 68 6621 7

[76] Sheng J.,Ma T.,Wu Y.,Wang M.. Programmable PROTAC delivery for precise and spatiotemporal protein degradation Chem. Commun. 2026 62 2414 27

[77] Hu H.,Busa P.,Zhao Y.,Zhao C.. Externally triggered drug delivery systems Smart Mater. Med. 2024 5 386 408 PMC12382459

[78] Mura S.,Nicolas J.,Couvreur P.. Stimuli-responsive nanocarriers for drug delivery Nat. Mater. 2013 12 991 1003

[79] Liu X.,He F.,Liu M.. New opportunities of stimulus-responsive smart nanocarriers in cancer therapy Nano Mater. Sci. 2024

[80] Cheng L.,Wang C.,Feng L.,Yang K.,Liu Z.. Functional nanomaterials for phototherapies of cancer Chem. Rev. 2014 114 10869 939

[81] Zhang L.,Wang D.,Yang K..et al. Mitochondria-targeted artificial “Nano-RBCs” for amplified synergistic cancer phototherapy by a single NIR irradiation Adv. Sci. 2018 5 1800049

[82] Castano A. P.,Mroz P.,Hamblin M. R.. Photodynamic therapy and anti-tumour immunity Nat. Rev. Cancer 2006 6 535 45 PMC2933780

[83] Sun B.,Bte Rahmat J. N.,Zhang Y.. Advanced techniques for performing photodynamic therapy in deep-seated tissues Biomaterials 2022 291 121875

[84] Li J.,Pu K.. Semiconducting polymer nanomaterials as near-infrared photoactivatable protherapeutics for cancer Acc. Chem. Res. 2020 53 752 62

[85] Mouret S.,Baudouin C.,Charveron M.,Favier A.,Cadet J.,Douki T.. Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation Proc. Natl. Acad. Sci. U. S. A. 2006 103 13765 70 PMC1564232

[86] Zhan J.,Li X.,Mu Y.,Yao H.,Zhu J. J.,Zhang J.. A photoactivatable upconverting nanodevice boosts the lysosomal escape of PROTAC degraders for enhanced combination therapy Biomater. Sci. 2024 12 3686 99

[87] He Q.,Zhou L.,Yu D..et al. Near-infrared-activatable PROTAC nanocages for controllable target protein degradation and on-demand antitumor therapy J. Med. Chem. 2023 66 10458 72

[88] Liu J.,Chen H.,Ma L..et al. Light-induced control of protein destruction by opto-PROTAC Sci. Adv. 2020 6 eaay5154 PMC7034987

[89] Wang W.,Zhu C.,Zhang B.,Feng Y.,Zhang Y.,Li J.. Self-assembled nano-PROTAC enables near-infrared photodynamic proteolysis for cancer therapy J. Am. Chem. Soc. 2023 145 16642 9

[90] Lu X.,Wang X.,Liao H.,Sha B.,Zhang Y.,Li J.. Tandem-activatable PROTAC prodrug for tumor biomarker-driven near-infrared opto-proteolysis Angew. Chem. Int. Ed. 2025 64 e202510641

[91] Li J.,Luo Y.,Zeng Z..et al. Precision cancer sono-immunotherapy using deep-tissue activatable semiconducting polymer immunomodulatory nanoparticles Nat. Commun. 2022 13 4032 PMC9276830

[92] Huang P.,Qian X.,Chen Y..et al. Metalloporphyrin-encapsulated biodegradable nanosystems for highly efficient magnetic resonance imaging-guided sonodynamic cancer therapy J. Am. Chem. Soc. 2017 139 1275 84

[93] Ouyang J.,Tang Z.,Farokhzad N..et al. Ultrasound mediated therapy: recent progress and challenges in nanoscience Nano Today 2020 35 100949

[94] Xu M.,Hu Y.,Wu J.,Liu J.,Pu K.. Sonodynamic nano-LYTACs reverse tumor immunosuppressive microenvironment for cancer immunotherapy J. Am. Chem. Soc. 2024 146 34669 80

[95] Zhang Q.,Bao C.,Cai X..et al. Sonodynamic therapy-assisted immunotherapy: a novel modality for cancer treatment Cancer Sci. 2018 109 1330 45

[96] Canavese G.,Ancona A.,Racca L..et al. Nanoparticle-assisted ultrasound: a special focus on sonodynamic therapy against cancer Chem. Eng. J. 2018 340 155 72 PMC6420022

[97] Fan X.,Jiao G.,Zhao W.,Jin P.,Li X.. Magnetic Fe₃O₄-graphene composites as targeted drug nanocarriers for pH-activated release Nanoscale 2013 5 1143 52

[98] Najafi N.,Kheirollah J.,Majidi H..et al. Enhancing magnetic drug targeting efficiency through computational analysis: Investigating Particle-RBC interaction and non-newtonian blood behavior J. Magn. Magn. Mater. 2024 600 172153

[99] Jiao W.,Dai L.,Yan B.,Lyu Y.,Fan H.,Liu X.. Heating up the immune battle: magnetic hyperthermia against cancer Fundam. Res. 2025 5 2401 5 PMC12744615

[100] Lapusan R.,Borlan R.,Focsan M.. Advancing MRI with magnetic nanoparticles: a comprehensive review of translational research and clinical trials Nanoscale Adv. 2024 6 2234 59 PMC11059564

[101] Lv J.,Yue R.,Liu H..et al. Enzyme-activated nanomaterials for MR imaging and tumor therapy Coord. Chem. Rev. 2024 510 215842

[102] Salahpour Anarjan F.. Active targeting drug delivery nanocarriers: ligands Nano-Struct. Nano-Objects 2019 19 100370

[103] Chen Z.,Kankala R. K.,Long L.,Xie S.,Chen A.,Zou L.. Current understanding of passive and active targeting nanomedicines to enhance tumor accumulation Coord. Chem. Rev. 2023 481 215051

[104] Huang L.,Zhang Q.,Long J.,Liu Z.,Sun X.. Construction of novel magnetic systems for cancer immunotherapy via cancer-immunity cycle circuits J. Control. Release 2025 378 38 59

[105] Zhang H.,Wang J.,Han R.,Sun B.,Luo C.. Bioorthogonal chemistry-driven anticancer nanotherapeutics Trends Chem. 2023 5 697 710

[106] Keppel P.,Hecko S.,Mikula H.. Click-triggered bioorthogonal bond-cleavage reactions Top. Curr. Chem. 2025 383 25 PMC12167358

[107] Oliveira B. L.,Guo Z.,Bernardes G. J. L.. Inverse electron demand Diels-Alder reactions in chemical biology Chem. Soc. Rev. 2017 46 4895 950

[108] Huang J.,Yao Z.,Li B.,Ping Y.. Targeted delivery of PROTAC-based prodrug activated by bond-cleavage bioorthogonal chemistry for microneedle-assisted cancer therapy J. Control. Release 2023 361 270 9

[109] Sletten E. M.,Bertozzi C. R.. Bioorthogonal chemistry: fishing for selectivity in a sea of functionality Angew. Chem. Int. Ed. 2009 48 6974 98 PMC2864149

[110] Blackman M. L.,Royzen M.,Fox J. M.. Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity J. Am. Chem. Soc. 2008 130 13518 9

[111] Xie S.,Zhu J.,Peng Y..et al. In vivo self-assembly of PROTACs by bioorthogonal chemistry for precision cancer therapy Angew. Chem. Int. Ed. 2025 64 e202421713

[112] Gao J.,Hou B.,Zhu Q..et al. Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy Nat. Commun. 2022 13 4318 PMC9325692

[113] Sun C.,Liu S.,Lau J. W.,Yang H.,Chen Y.,Xing B.. Inside Front Cover: Enzyme‐activated orthogonal proteolysis chimeras for tumor microenvironment‐responsive immunomodulation (Angew. Chem. Int. Ed. 22/2025) Angew. Chem. Int. Ed. 2025 64 e202510013

[114] Swetha K. L.,Roy A.. Tumor heterogeneity and nanoparticle-mediated tumor targeting: the importance of delivery system personalization Drug Deliv. Transl. Res. 2018 8 1508 26

[115] Li S.,Zeng Q.,Zhu S..et al. Engineering nano-PROTAC platforms: Self-assembly, stimuli-responsiveness, and targeted delivery for precision therapy Chem. Eng. J. 2026 531 174085

[116] Zhou T.,Gao Y.,Ma B..et al. Multi-stimuli activated PROTAC prodrug for controlled protein degradation with enhanced therapeutic effects Eur. J. Med. Chem. 2026 306 118571

[117] Shang Y.,Zhu L.,Xiao Y..et al. Logic gate activated lysosome targeting DNA nanodevice for controlled proteins degradation Adv. Funct. Mater. 2023 34 2311722

[118] Weng Z.,Yu J.,Liao Y.,Zhang Y.,Chen C.,Chen W.. Emerging strategies in smart nano-PROTAC for stimuli-responsive protein degradation and precision cancer therapy Nano Biomed. Eng. 2025 17 315 32

[119] Cai J.,Chen C.,Wang J..et al. PROTAC: a revolutionary technology propelling small molecule drugs into the next golden age Front. Oncol. 2025 15 1676414 PMC12597787

[120] Majumder J.,Minko T.. Multifunctional and stimuli-responsive nanocarriers for targeted therapeutic delivery Expert Opin. Drug Deliv. 2021 18 205 27 PMC7904578

[121] Zhou W.,Jia Y.,Liu Y.,Chen Y.,Zhao P.. Tumor microenvironment-based stimuli-responsive nanoparticles for controlled release of drugs in cancer therapy Pharmaceutics 2022 14 2346 PMC9694300

[122] Hu F.,Huang J.,Bing T..et al. Stimulus-responsive copper complex nanoparticles induce cuproptosis for augmented cancer immunotherapy Adv. Sci. 2024 11 e2309388

[123] Poyia F.,Neophytou C. M.,Christodoulou M. I.,Papageorgis P.. The role of tumor microenvironment in pancreatic cancer immunotherapy: current status and future perspectives Int. J. Mol. Sci. 2024 25 9555 PMC11395109

[124] Yang L.,Yang Y.,Zhang J..et al. Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy Signal Transduct. Target. Ther. 2024 9 275 PMC11486899

[125] Guan X.,Xu X.,Tao Y..et al. Dual targeting and bioresponsive nano-PROTAC induced precise and effective lung cancer therapy J. Nanobiotechnol. 2024 22 692 PMC11552110

[126] Zhang H. T.,Peng R.,Chen S..et al. Versatile nano-PROTAC-induced epigenetic reader degradation for efficient lung cancer therapy Adv. Sci. 2022 9 e2202039

[127] Wang Y.,Yao X.,Lu Y..et al. A PROTAC-based cuproptosis sensitizer in lung cancer therapy Adv. Mater. 2025 37 e2501435

[128] Mi P.. Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics Theranostics 2020 10 4557 88 PMC7150471

[129] Wang L.,Li J.,Zeng X..et al. Exogenous/endogenous stimuli-responsive antitumor prodrugs advance precision chemotherapy Bioorg. Med. Chem. 2026 132 118485

[130] Park B.,Choi J.,Lee J. H..et al. Reprogramming of cancer metabolism via photoresponsive nano-PROTAC enhances pyroptosis-mediated immunotherapy Signal Transduct. Target. Ther. 2025 10 310 PMC12464334

[131] Choi J.,Park B.,Park J. Y..et al. Light-Triggered PROTAC nanoassemblies for photodynamic IDO proteolysis in cancer immunotherapy Adv. Mater. 2024 36 e2405475

[132] Zhang C.,Zeng Z.,Cui D..et al. Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy Nat. Commun. 2021 12 2934 PMC8131624

[133] Fu Z.,Yang C.,Yang Y.,Pan M.,Hou H.,Li J.. Photodynamic enhancement of PROTAC prodrug activation in hypoxic tumors Acta Pharm. Sin. B. 2025 15 4945 60 PMC12491708

[134] Li Z.,Ren G.,Wang X..et al. Tumor microenvironment responsive nano-PROTAC for BRD4 degradation enhanced cancer photo-immunotherapy Biomaterials 2025 322 123387

[135] Lu S.,Shi Z.,Ding C..et al. BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy Biomaterials 2025 317 123101

[136] Gao J.,Jiang X.,Lei S..et al. A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy Nat. Commun. 2024 15 6608 PMC11298519

[137] Liu Y.,Wang H.,Ding M..et al. Ultrasound-activated PROTAC prodrugs overcome immunosuppression to actuate efficient deep-tissue sono-immunotherapy in orthotopic pancreatic tumor mouse models Nano Lett. 2024 24 8741 51

[138] Chen S.,Chen E.,Su J..et al. Magnetically navigated nano-PROTAC ameliorates acute lung injury J. Nanobiotechnol. 2025 23 622 PMC12486976

[139] Dey K.,Erwin N.,Molina N.,Chen H.,He M.,Zheng G.. Nano-TPD: Using nanoparticle-based systems to improve the delivery and therapeutic effect of targeted protein degraders Med. Chem. Res. 2025 34 2205 27

[140] Zeng S.,Zhang H.,Shen Z.,Huang W.. Photopharmacology of proteolysis-targeting chimeras: a new frontier for drug discovery Front. Chem. 2021 9 639176 PMC7987681

[141] Wang Z. W.,Liu Y.,Zhu X.. PhotoPROTACs: a novel biotechnology for cancer treatment Trends Cell Biol. 2020 30 749 51

[142] Zhang W.,Li S.,Yuan H.,Zhao J.. Advances in light-activated PROTACs and phototherapy-combined approaches for cancer treatment Eur. J. Med. Chem. 2026 302 118310

[143] Hua S.,de Matos M. B. C.,Metselaar J. M.,Storm G.. Current trends and challenges in the clinical translation of nanoparticulate nanomedicines: pathways for translational development and commercialization Front. Pharmacol. 2018 9 790 PMC6056679

[144] Baker A. G.,Ho A. P. T.,Itzhaki L. S.,Fruk L.. Nanoparticle-mediated targeted protein degradation: an emerging therapeutics technology Angew. Chem. Int. Ed. 2025 64 e202503958

[145] Agrahari V.,Agrahari V.. Facilitating the translation of nanomedicines to a clinical product: challenges and opportunities Drug Discov. Today 2018 23 974 91

[146] Joyce P.,Allen C. J.,Alonso M. J..et al. A translational framework to DELIVER nanomedicines to the clinic Nat. Nanotechnol. 2024 19 1597 611

[147] Sun T.,Jiang C.. Stimuli-responsive drug delivery systems triggered by intracellular or subcellular microenvironments Adv. Drug Delivery Rev. 2023 196 114773

[148] Hao J.,Li Y.,Huang L..et al. Smart nanoarchitectures for precision RNA delivery: harnessing endogenous and exogenous stimuli in cancer treatment Theranostics 2025 15 7747 78 PMC12316030

[149] Cabral H.,Li J.,Miyata K.,Kataoka K.. Controlling the biodistribution and clearance of nanomedicines Nat. Rev. Bioeng. 2023 2 214 32

[150] Fu F.,Crespy D.,Landfester K.,Jiang S.. In situ characterization techniques of protein corona around nanomaterials Chem. Soc. Rev. 2024 53 10827 51

[151] Ly P.,Ly K.,Phan H.,Nguyen H. H. T.,Duong V.,Nguyen H. V.. Recent advances in surface decoration of nanoparticles in drug delivery Front. Nanotechnol. 2024 6 1456939

[152] Zhang Q.,Kuang G.,Li W.,Wang J.,Ren H.,Zhao Y.. Stimuli-responsive gene delivery nanocarriers for cancer therapy NanoMicro. Lett. 2023 15 44 PMC9908819

[153] Wan J.,Huang L.,Cheng J.,Qi H.,Jin J.,Wang H.. Balancing the stability and drug activation in adaptive nanoparticles potentiates chemotherapy in multidrug-resistant cancer Theranostics 2021 11 4137 54 PMC7977460

[154] Chen Z.,Li H.,Bian Y..et al. Bioorthogonal catalytic patch Nat. Nanotechnol. 2021 16 933 41

[155] Li Y.,Vulpe C.,Lammers T.,Pallares R. M.. Assessing inorganic nanoparticle toxicity through omics approaches Nanoscale 2024 16 15928 45

[156] Carter P. J.,Quarmby V.. Immunogenicity risk assessment and mitigation for engineered antibody and protein therapeutics Nat. Rev. Drug Discov. 2024 23 898 913

[157] Mohamed M.,Abu Lila A. S.,Shimizu T..et al. PEGylated liposomes: immunological responses Sci. Technol. Adv. Mater. 2019 20 710 24 PMC6598536

[158] Miao G.,He Y.,Lai K..et al. Accelerated blood clearance of PEGylated nanoparticles induced by PEG-based pharmaceutical excipients J. Control. Release 2023 363 12 26

[159] Gaballa S. A.,Shimizu T.,Ando H..et al. Treatment-induced and pre-existing anti-peg antibodies: prevalence, clinical implications, and future perspectives J. Pharm. Sci. 2024 113 555 78

[160] Szebeni J.. Complement activation-related pseudoallergy caused by liposomes, micellar carriers of intravenous drugs, and radiocontrast agents Crit. Rev. Ther. Drug Carrier Syst. 2001 18 40

[161] Saxena S.,Sharma S.,Kumar G.,Thakur S.. Unravelling the complexity of CARPA: a review of emerging advancements in therapeutic strategies Arch. Dermatol. Res. 2025 317 439

[162] Szebeni J.. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals Mol. Immunol. 2014 61 163 73

[163] Liu X.,Zhang Y.,Ward L. D..et al. A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing Sci. Rep. 2021 11 15856

[164] Đorđević S.,Gonzalez M. M.,Conejos-Sánchez I..et al. Current hurdles to the translation of nanomedicines from bench to the clinic Drug Deliv. Transl. Res. 2022 12 500 25

[165] Wu X.,Shu Y.,Zheng Y..et al. Recent advances in nanomedicine: cutting-edge research on nano-PROTAC delivery systems for cancer therapy Pharmaceutics 2025 17 1037

[166] Jayaraj S.,Jiang W.,Mudalige T.. An Automated capillary electrophoresis based method for drug release profiling of liposomal doxorubicin J. Pharm. Sci. 2024 113 1088 93

[167] Overchuk M.,Weersink R. A.,Wilson B. C.,Zheng G.. Photodynamic and photothermal therapies: synergy opportunities for nanomedicine ACS Nano 2023 17 7979 8003

[168] Li X.,Lovell J. F.,Yoon J.,Chen X.. Clinical development and potential of photothermal and photodynamic therapies for cancer Nat. Rev. Clin. Oncol. 2020 17 657 74

[169] Reis M. E.,Bettencourt A.,Ribeiro H. M.. The regulatory challenges of innovative customized combination products Front. Med. 2022 9 821094

[170] Li H.,Shen X.,Chu Y.,Yuan P.,Shuai Q.. Challenging and new opportunities for prodrug technology Investig. New Drugs 2025 43 365 76

[171] Gupta D. K.,Tiwari A.,Yadav Y.,Soni P.,Joshi M.. Ensuring safety and efficacy in combination products: regulatory challenges and best practices Front. Med. Technol. 2024 6 1377443

[172] Arenas-Moreira M.,Ocaña A.,Bravo I.,Alonso-Moreno C.. PROTAC delivery systems: innovative approaches for cancer treatment Biomed. Pharmacother. 2026 194 118892

[173] Wang C.,Zhang Y.,Chen W.,Wu Y.,Xing D.. New-generation advanced PROTACs as potential therapeutic agents in cancer therapy Mol. Cancer 2024 23 110

[174] Grasso G.,Colella F.,Forciniti S..et al. Fluorescent nano- and microparticles for sensing cellular microenvironment: past, present and future applications Nanoscale Adv. 2023 5 4311 36

[175] Sabit H.,Pawlik T. M.,Radwan F..et al. Precision nanomedicine: navigating the tumor microenvironment for enhanced cancer immunotherapy and targeted drug delivery Mol. Cancer 2025 24 160

[176] Mao Y.,Xie J.,Yang F.,Luo Y.,Du J.,Xiang H.. Advances and prospects of precision nanomedicine in personalized tumor theranostics Front. Cell Dev. Biol. 2024 12 1514399

[177] Luo C.,He L.,Chen F..et al. Stimulus-responsive nanomaterials containing logic gates for biomedical applications Cell Rep. Phys. Sci. 2021 2 100350

[178] Tang L.,Yang Z.,Zhou Z..et al. A logic-gated modular nanovesicle enables programmable drug release for on-demand chemotherapy Theranostics 2019 9 1358 68

[179] Jiang C.,Zhao Z.,East A. K.,Bandyopadhyay S.,Jiang Z.,Chan J.. Logic-gated approach for targeted delivery and site-selective activation of photothermal agents in precision cancer treatment Chem. Sci. 2025 16 5155 65

[180] Mishra V.,Kumari N.,Vyas M.,Aljabali A. A. A.,Chattaraj A.,Mishra Y.. Advances in multimodal imaging techniques in nanomedicine: enhancing drug delivery precision RSC Adv. 2025 15 27187 209

[181] Saladino G. M.,Mangarova D. B.,Nernekli K..et al. Multimodal imaging approach to track theranostic nanoparticle accumulation in glioblastoma with magnetic resonance imaging and intravital microscopy Nanoscale 2025 17 9986 95

[182] Ju S.,Cho H. Y.. Biohybrid nanoparticle-based in situ monitoring of in vivo drug delivery Biosensors 2023 13 1017

[183] Yang Y.,Yue S.,Qiao Y..et al. Activable multi-modal nanoprobes for imaging diagnosis and therapy of tumors Front. Chem. 2020 8 572471

[184] Chen Y.,Zhang C.,Yu Z.,Hu K.,Zhou T.. Circumventing tumor immune evasion: coordinated immunotherapy via in situ tumor nanovaccines and local ablation Chem. Eng. J. 2025 523 168636

[185] Parvin N.,Joo S. W.,Mandal T. K.. Biodegradable and stimuli-responsive nanomaterials for targeted drug delivery in autoimmune diseases J. Funct. Biomater. 2025 16 24

[186] Zheng C.,Li M.,Ding J.. Challenges and opportunities of nanomedicines in clinical translation Bio Integration 2021 2 57 https://bio-integration.org/10-15212-bioi-2021-0016/ (accessed 2026-04-24).

[187] Han Y.,Kim D. H.,Pack S. P.. Nanomaterials in drug delivery: leveraging artificial intelligence and big data for predictive design Int. J. Mol. Sci. 2025 26 11121

[188] Chakroborty S.,Nath N.,Sahoo S..et al. A review of emerging trends in nanomaterial-driven AI for biomedical applications Nanoscale Adv. 2025 7 3619 30

[189] DeRidder L. B.,Hare K. A.,Lopes A..et al. Closed-loop automated drug infusion regulator: a clinically translatable, closed-loop drug delivery system for personalized drug dosing Med 2024 5 780 796.e10

[190] Paci M. M.,Saha T.,Djassemi O..et al. Smart closed-loop drug delivery systems Nat. Rev. Bioeng. 2025 3 816 34

[191] Mashayekhi H.,Nazari M.,Jafarinejad F.,Meskin N.. Deep reinforcement learning-based control of chemo-drug dose in cancer treatment Comput. Methods Programs Biomed. 2024 243 107884