Design and delivery of targeting chimeras therapeutics in managing central nervous system disorders

Abstract

Site-specific degradation by targeting chimeras (TACs) has become a desirable alternative to occupancy-driven inhibition for central nervous system (CNS) diseases due to the possibility of completely deactivating pathogenic proteins, rather than complete blocking. The catalytic mechanism of TACs is dynamic, meaning that they can provide sustained therapeutic effects at low doses in clearing key pathogenic proteins associated with CNS diseases, while resisting the development of resistance mechanisms. However, the physicochemical properties of TACs pose a high delivery question for the brain, limiting brain bioavailability and impairing clinical progress. To address this issue, this review presents the structure-function relations of TAC modules, focusing on their therapeutic potential in various CNS diseases such as glioblastoma, Alzheimer's disease, and Parkinson's disease, as well as the role of novel nanocarriers and delivery platforms in overcoming biological barriers. The review is intended to inform future brain-penetrant TAC therapeutics.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (82372113), the National Ten Thousand Talents Program for Young Top-notch Talents, Lingang Laboratory (Grant No. LGL-2614-09), the Natural Science Foundation for Distinguished Young Scholars of Jiangsu Province (BK20240096), and the Joint Fund of Zhejiang Provincial Natural Science Foundation of China (LKLY25H180014). In addition, we thank the Jiangsu 333 High-level Talent Training Project ([2022] 3-16-190), Fundamental Research Funds for the Central Universities (2632025PY02, 2632026TD05), China Postdoctoral Science Foundation (Grant Nos 2025T180968 and 2025M783610).

Ethical statements

Not applicable.

Author contributions

The authors confirm their contributions to the work as follows: study conception: Ding Y, Han G, Gu X; writing original draft: Liu S, Xu W, Wang M; review and editing: Ding Y, Han G, Gu X. All authors reviewed the results and approved the final version of the manuscript.

Data availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Conflict of interest

The authors declare that they have no conflict of interest.

References

[1] Vatansever S, Schlessinger A, Wacker D, Kaniskan HÜ, Jin J, et al. 2021. Artificial intelligence and machine learning-aided drug discovery in central nervous system diseases: state-of-the-arts and future directions. Medicinal Research Reviews 41: 1427-1473

[2] Naqvi S, Panghal A, Flora SJS. 2020. Nanotechnology: a promising approach for delivery of neuroprotective drugs. Frontiers in Neuroscience 14: 494

[3] Zhao L, Zhao J, Zhong K, Tong A, Jia D. 2022. Targeted protein degradation: mechanisms, strategies and application. Signal Transduction and Targeted Therapy 7: 113

[4] Guan X, Yu XY, Zhang L. 2026. A breakthrough in NSCLC therapy: targeted protein degradation of CD26 via PROTACs . eBioMedicine 123: 106082

[5] Wang X, Chen S, Xia X, Du Y, Wei Y, et al. 2025. Lysosome-targeting protein degradation through endocytosis pathway triggered by polyvalent nano-chimera for AD therapy. Advanced Materials 37: 2411061

[6] Xiao Y, He Z, Li W, Chen D, Niu X, et al. 2025. A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy. Nature Communications 16: 1388

[7] Bae TH, Sung KW, Pham TM, Najy AJ, Zamiri A, et al. 2025. An autophagy-targeting chimera induces degradation of androgen receptor mutants and AR-v7 in castration-resistant prostate cancer. Cancer Research 85: 342-359

[8] Song Z, Gao Y, Zou X, Wang Z, Zhang S, et al. 2026. Inducing potent ferroptosis in cancer cells by manipulation of ferritinophagy with a ferritin-targeted ATTEC. Journal of Controlled Release 389: 114450

[9] Duan Y, Cai MY, Xu J, Hu Q. 2025. Rational design of the linkers in targeting chimeras. Chemical Science 16: 17595-17610

[10] Chen Y, Tandon I, Heelan W, Wang Y, Tang W, et al. 2022. Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation. Chemical Society Reviews 51: 5330-5350

[11] Liang X, Ren H, Han F, Liang R, Zhao J, et al. 2024. The new direction of drug development: degradation of undruggable targets through targeting chimera technology. Medicinal Research Reviews 44: 632-685

[12] Pike A, Williamson B, Harlfinger S, Martin S, McGinnity DF. 2020. Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective. Drug Discovery Today 25: 1793-1800

[13] Drummond ML, Williams CI. 2019. In silico modeling of PROTAC-mediated ternary complexes: validation and application . Journal of Chemical Information and Modeling 59: 1634-1644

[14] Kong NR, Jones LH. 2023. Clinical translation of targeted protein degraders. Clinical Pharmacology & Therapeutics 114: 558-568

[15] Wang C, Zhang Y, Wang J, Xing D. 2022. VHL-based PROTACs as potential therapeutic agents: recent progress and perspectives. European Journal of Medicinal Chemistry 227: 113906

[16] Ji CH, Lee MJ, Kim HY, Heo AJ, Park DY, et al. 2022. Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera) . Autophagy 18: 2259-2262

[17] Zou Y, Ma D, Wang Y. 2019. The PROTAC technology in drug development. Cell Biochemistry and Function 37: 21-30

[18] An S, Fu L. 2018. Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. eBioMedicine 36: 553-562

[19] Cromm PM, Crews CM. 2017. Targeted protein degradation: from chemical biology to drug discovery. Cell Chemical Biology 24: 1181-1190

[20] Jin J, Wu Y, Chen J, Shen Y, Zhang L, et al. 2020. The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination. Theranostics 10: 10141-10153

[21] Lazo JS, Sharlow ER. 2016. Drugging undruggable molecular cancer targets. Annual Review of Pharmacology and Toxicology 56: 23-40

[22] Luo H, Tian Y, Abdullah R, Zhang B, Ma Y, et al. 2025. Advancing design strategy of PROTACs for cancer therapy. MedComm 6: e70258

[23] Keefe AD, Pai S, Ellington A. 2010. Aptamers as therapeutics. Nature Reviews Drug Discovery 9: 537-550

[24] Cao C, Li A, Xu C, Wu B, Yao L, et al. 2025. Engineering artificial non-coding RNAs for targeted protein degradation. Nature Chemical Biology 21: 393-401

[25] Schaefer D, Cheng X. 2023. Recent advances in covalent drug discovery. Pharmaceuticals 16: 663

[26] Grimster NP. 2021. Covalent PROTACs: the best of both worlds? RSC Medicinal Chemistry 12: 1452-1458

[27] Ebadi P, Stratton CM, Olsen SK. 2025. E3 ubiquitin ligases in signaling, disease, and therapeutics. Trends in Biochemical Sciences 50: 960-976

[28] Wang Y, Jiang X, Feng F, Liu W, Sun H. 2020. Degradation of proteins by PROTACs and other strategies. Acta Pharmaceutica Sinica B 10: 207-238

[29] Sobierajski T, Małolepsza J, Pichlak M, Gendaszewska-Darmach E, Błażewska KM. 2024. The impact of E3 ligase choice on PROTAC effectiveness in protein kinase degradation. Drug Discovery Today 29: 104032

[30] Lee J, Lee Y, Jung YM, Park JH, Yoo HS, et al. 2022. Discovery of E3 ligase ligands for target protein degradation. Molecules 27: 6515

[31] Kannt A, Đikić I. 2021. Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation. Cell Chemical Biology 28: 1014-1031

[32] Ahn G, Riley NM, Kamber RA, Wisnovsky S, Moncayo von Hase S, et al. 2023. Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras. Science 382: eadf6249

[33] Teng F, Liu J, Cui T, Tan X, Liu K, et al. 2026. Efficient amyloid-β degradation in Alzheimer's disease using SPYTACs. Cell 189: 1-19

[34] Lu RHH, Krishna J, Alp Y, Thayumanavan S. 2026. Polymeric lysosome-targeting chimeras (PolyTACs): extracellular targeted protein degradation without co-opting lysosome-targeting receptors. Journal of the American Chemical Society 148: 1259-1270

[35] Webb T, Craigon C, Ciulli A. 2022. Targeting epigenetic modulators using PROTAC degraders: current status and future perspective. Bioorganic & Medicinal Chemistry Letters 63: 128653

[36] Hu Z, Chen PH, Li W, Douglas T, Hines J, et al. 2023. Targeted dephosphorylation of tau by phosphorylation targeting chimeras (PhosTACs) as a therapeutic modality. Journal of the American Chemical Society 145: 4045-4055

[37] Zheng J, Tian N, Liu F, Zhang Y, Su J, et al. 2021. A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies. Signal Transduction and Targeted Therapy 6: 269

[38] Tong Y, Zhang P, Yang X, Liu X, Zhang J, et al. 2024. Decreasing the intrinsically disordered protein α-synuclein levels by targeting its structured mRNA with a ribonuclease-targeting chimera. Proceedings of the National Academy of Sciences of the United States of America 121: e2306682120

[39] Xia LW, Ba MY, Liu W, Cheng W, Hu CP, et al. 2019. Triazol: a privileged scaffold for proteolysis targeting chimeras. Future Medicinal Chemistry 11: 2919-2973

[40] Ayinde OR, Sharpe C, Stahl E, Tokarski RJ II, Lerma JR, et al. 2023. Examination of the impact of triazole position within linkers on solubility and lipophilicity of a CDK9 degrader series. ACS Medicinal Chemistry Letters 14: 936-942

[41] Song C, Jiao Z, Hou Z, Wang R, Lian C, et al. 2023. Selective protein of interest degradation through the split-and-mix liposome proteolysis targeting chimera approach. Journal of the American Chemical Society 145: 21860-21870

[42] Liu J, Chen H, Ma L, He Z, Wang D, et al. 2020. Light-induced control of protein destruction by opto-PROTAC. Science Advances 6: eaay5154

[43] Dong Y, Ma T, Xu T, Feng Z, Li Y, et al. 2024. Characteristic roadmap of linker governs the rational design of PROTACs. Acta Pharmaceutica Sinica B 14: 4266-4295

[44] Zhong G, Chang X, Xie W, Zhou X. 2024. Targeted protein degradation: advances in drug discovery and clinical practice. Signal Transduction and Targeted Therapy 9: 308

[45] Haridas V, Dutta S, Munjal A, Singh S. 2024. Inhibitors to degraders: changing paradigm in drug discovery. iScience 27: 109574

[46] Ruschak AM, Religa TL, Breuer S, Witt S, Kay LE. 2010. The proteasome antechamber maintains substrates in an unfolded state. Nature 467: 868-871

[47] Al Mamun A, Uddin MS, Kabir MT, Khanum S, Sarwar MS, et al. 2020. Exploring the promise of targeting ubiquitin-proteasome system to combat Alzheimer's disease. Neurotoxicity Research 38: 8-17

[48] Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, et al. 2022. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nature Neuroscience 25: 688-701

[49] Ahn G, Banik SM, Miller CL, Riley NM, Cochran JR, et al. 2021. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nature Chemical Biology 17: 937-946

[50] Liu H, Dai C, Fan Y, Guo B, Ren K, et al. 2017. From autophagy to mitophagy: the roles of P62 in neurodegenerative diseases. Journal of Bioenergetics and Biomembranes 49: 413-422

[51] Nematullah M, Hoda MN, Khan F. 2018. Protein phosphatase 2A: a double-faced phosphatase of cellular system and its role in neurodegenerative disorders. Molecular Neurobiology 55: 1750-1761

[52] Fan G, Chen S, Zhang Q, Yu N, Shen Z, et al. 2025. Proteolysis-targeting chimera (PROTAC): current applications and future directions. MedComm 6: e70401

[53] Chi KN, McKay RR, Sandhu S, Arranz Arija JA, Barthelemy P, et al. 2025. A phase 3 trial of the androgen receptor ligand-directed degrader, BMS-986365, versus investigator's choice in patients with metastatic castration-resistant prostate cancer (CA071-1000 - rechARge). Journal of Clinical Oncology 43: TPS5119

[54] Rathkopf D, Patel MR, Choudhury AD, Rasco D, Lakhani NJ, et al. 2024. 1597MO Clinical activity of BMS-986365 (CC-94676), a dual androgen receptor (AR) ligand-directed degrader and antagonist, in heavily pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Annals of Oncology 35: S962-S963

[55] Petrylak DP, McKean M, Lang JM, Gao X, Dreicer R, et al. 2024. ARV-766, a proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC): Initial results of a phase 1/2 study. Journal of Clinical Oncology 42: 5011

[56] Agarwal S, McDonald AA, Campbell V, Chen D, Davis J, et al. 2025. Pharmacokinetics and pharmacodynamics of KT-474, a novel selective interleukin-1 receptor-associated Kinase 4 (IRAK4) degrader, in healthy adults. Clinical and Translational Science 18: e70181

[57] Chen L, Luo R, Ma L, Xu Y, Cao J, et al. 2024. Discovery of LC-MI-3: a potent and orally bioavailable degrader of interleukin-1 receptor-associated kinase 4 for the treatment of inflammatory diseases. Journal of Medicinal Chemistry 67: 8060-8076

[58] Groocock L, Deb G, Zhu J, Gamez J, Castiglioni P, et al. 2024. BMS-986458 a potential first-in-class, highly selective, potent and well tolerated BCL6 ligand directed degrader (LDD) demonstrates multimodal anti-tumor efficacy for the treatment of B-cell non-Hodgkin's lymphoma. Blood 144: 957

[59] Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, et al. 2024. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science 383: eadi5798

[60] Rallabandi NC, Panpatil D, Gahtory D, Navik U, Kumar R. 2025. EGFR molecular degraders: preclinical successes and the road ahead. Future Medicinal Chemistry 17: 633-636

[61] Ren J, Wang J, Xu S, Liu J, Zhang Y, et al. 2025. Abstract 400: Preclinical development of TQB3019: a potent and selective oral BTK degrader leveraging the OAPD® platform to overcome acquired resistance mutations. Cancer Research 85: 400

[62] Yap TA, Gutierrez M, Iams WT, Moreno V, Hernandez Guerrero T, et al. 2025. A phase 2 safety and efficacy study of PRT3789 in combination with pembrolizumab in patients with advanced or metastatic solid tumors and a SMARCA4 mutation. Journal of Clinical Oncology 43: TPS8667

[63] Sen S, Hezel AF, Kasi A, Lakhani NJ, Spira AI, et al. 2025. Trial in progress: phase 1 study of the selective protein degrader ASP4396 in patients with locally advanced or metastatic solid tumors with KRAS G12D mutations. Journal of Clinical Oncology 43: TPS3178

[64] Nagashima T, Yoshinari T, Nishizono Y, Tasaki M, Inamura K, et al. 2023. Abstract 5735: Novel KRAS G12D degrader ASP3082 demonstrates in vivo, dose-dependent KRAS degradation, KRAS pathway inhibition, and antitumor efficacy in multiple KRAS G12D-mutated cancer models . Cancer Research 83: 5735

[65] Feng X, Wang Y, Long T, Bai L, Yang X, et al. 2023. P1239: Bruton tyrosine kinase (BTK) protein degrader BGB-16673 is less apt to cause, and able to overcome variable BTK resistance mutations compared to other BTK inhibitors (BTKi). HemaSphere 7: e368855c

[66] Salvaris RT, Brennan J, Lewis KL. 2025. BTK is the target that keeps on giving: a review of BTK-degrader drug development, clinical data, and future directions in CLL. Cancers 17: 557

[67] Guo Y, Cheng R, Wang Y, Gonzalez ME, Zhang H, et al. 2024. Regulation of EZH2 protein stability: new mechanisms, roles in tumorigenesis, and roads to the clinic. eBioMedicine 100: 104972

[68] Chi KN, McKay RR, Sandhu S, Arranz JA, Barthélémy P, et al. 2025. rechARge: a randomized phase III trial of the androgen receptor ligand-directed degrader, BMS-986365, vs investigator's choice in patients with mCRPC. Future Oncology 21: 1771-1777

[69] Yamada K, Kihara T, Shinsato K, Yasui H, Shino M, et al. 2025. Nasal powder formulation employing microenvironmental pH-modifier for rapid absorption of mirtazapine. Pharmaceutical Science Advances 3: 100068

[70] Lu D, Sun Y, Luan Y, He W. 2024. Rational design of siRNA-based delivery systems for effective treatment of brain diseases. Pharmaceutical Science Advances 2: 100041

[71] Xu J, Ma C, Hua M, Li J, Xiang Z, et al. 2022. CNS and CNS diseases in relation to their immune system. Frontiers in Immunology 13: 1063928

[72] Meyer AH, Feldsien TM, Mezler M, Untucht C, Venugopalan R, et al. 2023. Novel developments to enable treatment of CNS diseases with targeted drug delivery. Pharmaceutics 15: 1100

[73] Ma K, Han XX, Yang XM, Zhou SL. 2021. Proteolysis targeting chimera technology: a novel strategy for treating diseases of the central nervous system. Neural Regeneration Research 16: 1944-1949

[74] Lin J, Jin J, Shen Y, Zhang L, Gong G, et al. 2021. Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins. Theranostics 11: 8337-8349

[75] Assaad F, Salma A, Mrad M. 2025. Epidemiological profile of adult primary brain tumors. Surgical Neurology International 16: 310

[76] Yang T, Hu Y, Miao J, Chen J, Liu J, et al. 2022. A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization . Acta Pharmaceutica Sinica B 12: 2658-2671

[77] Yuan Z, Guo M, Zhang Y, Deng Y, Sun B, et al. 2025. MAGL targeted PROTAC degrader simultaneously enhances P53 for synergistic treatment of glioblastoma stem cell. Cell Death Discovery 11: 109

[78] Yin J, Kim SS, Choi E, Oh YT, Lin W, et al. 2020. ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages. Nature Communications 11: 2978

[79] Zhai L, Bell A, Ladomersky E, Lauing KL, Bollu L, et al. 2021. Tumor cell IDO enhances immune suppression and decreases survival independent of tryptophan metabolism in glioblastoma. Clinical Cancer Research 27: 6514-6528

[80] Bollu LR, Bommi PV, Monsen PJ, Zhai L, Lauing KL, et al. 2022. Identification and characterization of a novel indoleamine 2,3-dioxygenase 1 protein degrader for glioblastoma. Journal of Medicinal Chemistry 65: 15642-15662

[81] Fang Y, Wang J, Zhao M, Zheng Q, Ren C, et al. 2022. Progress and challenges in targeted protein degradation for neurodegenerative disease therapy. Journal of Medicinal Chemistry 65: 11454-11477

[82] Congdon EE, Ji C, Tetlow AM, Jiang Y, Sigurdsson EM. 2023. Tau-targeting therapies for Alzheimer disease: current status and future directions. Nature Reviews Neurology 19: 715-736

[83] Zhang ZY, Harischandra DS, Wang R, Ghaisas S, Zhao JY, et al. 2023. TRIM11 protects against tauopathies and is down-regulated in Alzheimer's disease. Science 381: eadd6696

[84] Wang W, Zhou Q, Jiang T, Li S, Ye J, et al. 2021. A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models. Theranostics 11: 5279-5295

[85] Qu L, Li S, Ji L, Luo S, Ding M, et al. 2021. Discovery of PT-65 as a highly potent and selective proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease. European Journal of Medicinal Chemistry 226: 113889

[86] Schönfeld J, Brunst S, Ciomirtan L, Willmer L, Chromik MA, et al. 2025. Structure-based design of PROTACS for the degradation of soluble epoxide hydrolase. Journal of Medicinal Chemistry 68: 13728-13749

[87] Lee J, Sung KW, Bae EJ, Yoon D, Kim D, et al. 2023. Targeted degradation of α-synuclein aggregates in Parkinson's disease using the AUTOTAC technology. Molecular Neurodegeneration 18: 41

[88] Xu Z, Huang X, Zhu Z, Liang F, Hu H, et al. 2025. Elevated blood microplastics and their potential association with Parkinson's disease. Journal of Hazardous Materials 500: 140431

[89] Pedrini M, Iannielli A, Meneghelli L, Passarella D, Broccoli V, et al. 2023. Synthesis and preliminary characterization of putative Anle138b-centered PROTACs against α-synuclein aggregation. Pharmaceutics 15: 1467

[90] Lind-Holm Mogensen F, Scafidi A, Poli A, Michelucci A. 2023. PARK7/DJ-1 in microglia: implications in Parkinson's disease and relevance as a therapeutic target. Journal of Neuroinflammation 20: 95

[91] Jia Y, Oyken M, Kim RQ, Tjokrodirijo RTN, de Ru AH, et al. 2024. Development of inhibitors, probes, and PROTAC provides a complete toolbox to study PARK7 in the living cell. Journal of Medicinal Chemistry 67: 7935-7953

[92] Ge R, Chen M, Wu S, Huang S, Zhou P, et al. 2025. DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases. Nature Communications 16: 4683

[93] Mackenzie IR, Rademakers R, Neumann M. 2010. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. The Lancet Neurology 9: 995-1007

[94] Rezvykh AP, Ustyugov AA, Chaprov KD, Teterina EV, Nebogatikov VO, et al. 2023. Cytoplasmic aggregation of mutant FUS causes multistep RNA splicing perturbations in the course of motor neuron pathology. Nucleic Acids Research 51: 5810-5830

[95] Xu X, Shen D, Gao Y, Zhou Q, Ni Y, et al. 2021. A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed? Translational Neurodegeneration 10: 29

[96] Tseng YL, Lu PC, Lee CC, He RY, Huang YA, et al. 2023. Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera . Journal of Biomedical Science 30: 27

[97] Xiao F, Tan X, He A, Zhou Y, Xu K, et al. 2026. Metabolites released from apoptotic cells in central nervous system orchestrates the pathological process of Alzheimer disease through improving autophagy. Autophagy 22: 779-794

[98] Wen J, Zhao M, Xiao Y, Li S, Hu W. 2024. OATP1A2 mediates Aβ1-42 transport and may be a novel target for the treatment of Alzheimer's disease. Frontiers in Pharmacology 15: 1443789

[99] Silva-Llanes I, Rodríguez-López S, González-Naranjo P, del Sastre E, López MG, et al. 2025. Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model. Brain, Behavior, and Immunity 127: 251-268

[100] Fang X, Jin H, Wang J, Zhang R, Li B. 2025. Gating mechanism of the two-pore-domain potassium channel THIK1. Nature Structural & Molecular Biology 32: 1175-1182

[101] Tan S, Wang D, Fu Y, Zheng H, Liu Y, et al. 2023. Targeted clearance of mitochondria by an autophagy-tethering compound (ATTEC) and its potential therapeutic effects. Science Bulletin 68: 3013-3026

[102] Jin Y, Han G, Gao Y, Cheng H, Sun C, et al. 2025. Serum-tolerant polymeric complex for stem-cell transfection and neural differentiation. Nature Communications 16: 2022

[103] Bu S, Ji J, Yang M, Sun J, Zhang J, et al. 2024. Chemical composition and neuroprotective activity of hemp seed aqueous extract and their chemotaxonomic significance. Pharmaceutical Science Advances 2: 100051

[104] Pan M, Fu Z, Hou H, Yang C, Li J. 2025. Proteolysis-targeting chimera (PROTAC): a revolutionary tool for chemical biology research. Small Methods 9: 2500402

[105] Hu Z, Crews CM. 2022. Recent developments in PROTAC-mediated protein degradation: from bench to clinic. ChemBioChem 23: e202100270

[106] Yao Y, Xu Z, Ding H, Yang S, Chen B, et al. 2025. Carrier-free nanoparticles − new strategy of improving druggability of natural products. Journal of Nanobiotechnology 23: 108

[107] Jeong J, Cho H, Moon Y, Shim N, Kim J, et al. 2026. Effective degradation of wild-type and mutant EGFR using self-assembling peptide-derived PROTAC nanoparticles (NanoTACs) for cancer therapy. Advanced Materials 38: e16974

[108] Jang Y, Choi J, Park B, Park JY, Lee JH, et al. 2025. Activatable PROTAC nanoassembly for photodynamic PTP1B proteolysis enhances glioblastoma immunotherapy. Acta Pharmaceutica Sinica B 15: 4886-4899

[109] Jin T, Li D, Yang T, Liu F, Kong J, et al. 2019. PTPN1 promotes the progression of glioma by activating the MAPK/ERK and PI3K/AKT pathways and is associated with poor patient survival. Oncology Reports 42: 717-725

[110] Wiede F, Lu KH, Du X, Zeissig MN, Xu R, et al. 2022. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell antitumor immunity. Cancer Discovery 12: 752-773

[111] Digiovanni S, Lorenzati M, Bianciotto OT, Godel M, Fontana S, et al. 2024. Blood-brain barrier permeability increases with the differentiation of glioblastoma cells in vitro . Fluids and Barriers of the CNS 21: 89

[112] Cuevas E, Rosas-Hernandez H, Burks SM, Ramirez-Lee MA, Guzman A, et al. 2019. Amyloid Beta 25-35 induces blood-brain barrier disruption in vitro . Metabolic Brain Disease 34: 1365-1374

[113] Zhang YL, Wang J, Zhang ZN, Su Q, Guo JH. 2022. The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer's disease. Neural Regeneration Research 17: 2355-2363

[114] Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. 2019. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nature Reviews Neurology 15: 501-518

[115] Yu W, Xuan C, Liu B, Zhou L, Yin N, et al. 2023. Carrier-free programmed spherical nucleic acid for effective ischemic stroke therapy via self-delivery antisense oligonucleotide . Nano Research 16: 735-745

[116] Yu W, Che C, Yang Y, Zhao Y, Liu J, et al. 2025. Bioactive self-assembled nanoregulator enhances hematoma resolution and inhibits neuroinflammation in the treatment of intracerebral hemorrhage. Advanced Science 12: e2408647

[117] Ma F, Yang L, Sun Z, Chen J, Rui X, et al. 2020. Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection. Science Advances 6: eabb4429

[118] Heneka MT, van der Flier WM, Jessen F, Hoozemanns J, Thal DR, et al. 2025. Neuroinflammation in Alzheimer disease. Nature Reviews Immunology 25: 321-352

[119] Gong B, Zhang W, Cong W, Gu Y, Ji W, et al. 2024. Systemic administration of neurotransmitter-derived lipidoids-PROTACs-DNA nanocomplex promotes tau clearance and cognitive recovery for Alzheimer's disease therapy. Advanced Healthcare Materials 13: e2400149

[120] He Y, Zan X, Miao J, Wang B, Wu Y, et al. 2022. Enhanced anti-glioma efficacy of doxorubicin with BRD4 PROTAC degrader using targeted nanoparticles. Materials Today Bio 16: 100423

[121] Donati B, Lorenzini E, Ciarrocchi A. 2018. BRD4 and cancer: going beyond transcriptional regulation. Molecular Cancer 17: 164

[122] García Jiménez D, Rossi Sebastiano M, Vallaro M, Mileo V, Pizzirani D, et al. 2022. Designing soluble PROTACs: strategies and preliminary guidelines. Journal of Medicinal Chemistry 65: 12639-12649

[123] Guo Y, You H, Li Y, Zhou Z, Tian Z, et al. 2025. Polymer-engineered PROTAC nanovehicles amplify synergistic effects with temozolomide by BRD4 degradation. Biomaterials Science 13: 5001-5016

[124] Ruan C, Liu L, Lu Y, Zhang Y, He X, et al. 2018. Substance P-modified human serum albumin nanoparticles loaded with paclitaxel for targeted therapy of glioma. Acta Pharmaceutica Sinica B 8: 85-96

[125] Yu W, Gong E, Wang C, Che C, Zhao Y, et al. 2024. In situ implantable DNA hydrogel for diagnosis and therapy of postoperative rehemorrhage following intracerebral hemorrhage surgery . Science Advances 10: eado3919

[126] Wang WD, Guo YY, Yang ZL, Su GL, Sun ZJ. 2023. Sniping cancer stem cells with nanomaterials. ACS Nano 17: 23262-23298

[127] Gao Y, Shi W, Klawa SJ, Daly ML, Samulski ET, et al. 2025. Reversible metamorphosis of hierarchical DNA-inorganic crystals. Nature Nanotechnology 20: 1813-1821

[128] Kim MG, Park JY, Shim G, Choi HG, Oh YK. 2015. Biomimetic DNA nanoballs for oligonucleotide delivery. Biomaterials 62: 155-163

[129] Xu Q, Hu X, Ullah I, Lin T, Liu Y, et al. 2025. Biomimetic hybrid PROTAC nanovesicles block multiple DNA repair pathways to overcome temozolomide resistance against orthotopic glioblastoma. Advanced Materials 37: 2504253

[130] Erwin N, De U, Xiao Y, Wang L, Maharjan CK, et al. 2025. Proteolysis targeting chimera loaded extracellular vesicles for developing triple negative breast cancer treatment. Journal of Extracellular Vesicles 14: e70211

[131] Silva RO, Haddad M, Counil H, Zaouter C, Patten SA, et al. 2025. Exploring the potential of plasma and adipose mesenchymal stem cell-derived extracellular vesicles as novel platforms for neuroinflammation therapy. Journal of Controlled Release 377: 880-898

[132] Jin Y, Fan J, Wang R, Wang X, Li N, et al. 2023. Ligation to scavenging strategy enables on-demand termination of targeted protein degradation. Journal of the American Chemical Society 145: 7218-7229

[133] González-Gallego J, Todorov-Völgyi K, Müller SA, Antesberger S, Todorov MI, et al. 2026. A fully iPS-cell-derived 3D model of the human blood-brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions. Nature Neuroscience 29: 479-492

[134] Hoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, et al. 2013. Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. Journal of Pharmaceutical Sciences 102: 3343-3355