Charge shielding and targeted delivery strategies of cationic carriers
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摘要:
阳离子载体因其优异的载药能力和递送性能，在药物递送领域具有广泛应用前景。然而，其高密度正电荷引发的系统毒性与非特异性摄取等问题仍是临床转化的关键障碍。近年来，电荷屏蔽与刺激响应策略的兴起为其生物相容性与靶向性调控提供了有效路径。本文系统回顾了化学修饰、天然高分子包覆及仿生膜策略在电荷屏蔽中的应用，进一步探讨pH、酶、ROS等内源性以及光、超声等外源性刺激响应机制在精准激活释放中的作用。在多模块协同与智能平台构建方面，阳离子载体正逐步从实验室探索迈向临床转化。本文对相关研究工作的临床转化前景及关键技术瓶颈进行了探讨，以期为下一代智能递送系统的设计提供理论框架与参考。
Abstract:Cationic carriers have demonstrated broad application prospects in drug delivery due to their excellent drug-loading capacity and delivery performance. However, their high-density positive surface charge often leads to systemic toxicity and nonspecific uptake, posing significant barriers to clinical translation. In recent years, the emergence of charge shielding and stimuli-responsive strategies has provided effective avenues for modulating biocompatibility and targeting specificity. This review systematically summarizes the applications of chemical modification, natural polymer coating, and biomimetic membrane strategies in charge shielding. Furthermore, it explores the roles of endogenous stimuli such as pH, enzymes, and reactive oxygen species, as well as exogenous triggers like light and ultrasound, in achieving precise activation and controlled release. With the integration of multi-functional modules and the development of intelligent delivery platforms, cationic carriers are progressively advancing from laboratory research toward clinical translation. This review also discusses the translational potential and critical technical bottlenecks of related delivery systems, aiming to provide a theoretical framework and some reference for the design of next-generation smart delivery systems.
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Keywords:
- cationic carrier /
- charge shielding /
- stimuli-responsive /
- smart delivery /
- clinical translation
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表 1 不同电荷屏蔽策略的比较
屏蔽类型 机 制 材 料 优 势 局限性 适用场景 化学修饰型屏蔽 共价接枝中性分子
屏蔽正电荷PEG、氟化聚合物等 1. 修饰位点明确；
2. 屏蔽效率可控；
3. 血液循环时间长；
4. 工艺可控性强，
适合大规模生产1. 化学修饰过程复杂；
2. 结构不可逆；
3. 免疫原性；
4. 释放响应性较弱须精准控制电荷密度，
对稳定性要求高的场景天然高分子
复合型屏蔽静电或氢键复合，
形成亲水包覆层HA、CS衍生物、
白蛋白等1. 毒性低，安全性良好；
2. 生物降解性优异，
生物相容性高；
3. 原料易于获得，
成本低廉1. 载药量有限；
2. 结构稳定性较差；
3. 批次一致性欠佳局部给药、对安全性
要求高的场景细胞膜包覆屏蔽 膜融合，形成天然
负电性外壳红细胞膜、肿瘤细胞膜、
杂化细胞膜等1. 功能整合度高；
2. 免疫隐匿性良好，
同源靶向性强；
3. 可设计性强1. 制备工艺复杂，技术壁垒高；
2. 材料一致性可和重复性低；
3. 规模化生产困难；
4. 成本高昂；
5. 储存运输困难长循环递送、靶向递送、
异质性微环境治疗场景
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表 2 一些基于阳离子载体材料递送的药物的临床应用进展
公 司 商品名 递送载体 阳离子载体材料 疾病领域 药 物 最高研发
状态临床试验登记号 Alnylam onpattro 脂质纳米颗粒 阳离子脂质
DLin-MC3-DMA家族性淀粉样多发性神经病变 siRNA 已上市 — BioNTech Comirnaty 脂质纳米颗粒 阳离子脂质ALC-0315 COVID-19 mRNA 已上市 — Moderna Spikevax 脂质纳米颗粒 阳离子脂质SM-102 COVID-19 mRNA 已上市 — Moderna mRESVIA® 脂质纳米颗粒 阳离子脂质SM-102 呼吸道合胞病毒感染 mRNA 已上市 — 石药集团 度恩泰 脂质纳米颗粒 阳离子脂质（自研） COVID-19 mRNA 已上市 — 斯微生物 斯维尔克 脂质纳米载体 脂质多聚复合物LPP COVID-19 mRNA 已上市 — Revance Therapeutics, Inc. Daxi 阳离子肽 RTP004 中度至重度眉间纹 肉毒杆菌
毒素A已上市 — Sarepta Therapeutics Eteplirsen 细胞穿膜肽 CTCCAACATCAAGGA
AGATGGCATTTCTAG杜氏肌营养不良 磷酰二胺
吗啉寡聚物已上市 — Xigen SA XG-102 细胞穿膜肽 TAT 眼部炎症和疼痛 JNK抑制剂 Ⅲ期临床 NCT02508337 NoNO Inc. NA-1 细胞穿膜肽 TAT 重度急性缺血性
脑卒中PSD-95
抑制剂Ⅲ期临床 NCT02930018 Auris Medical AM-111 细胞穿膜肽 TAT 急性内耳听力损失 JNK抑制剂 Ⅲ期临床 NCT02561091 Avelas Bioscience AVB-620 细胞穿膜肽 ACPP 乳腺癌术中可视化 Cy5、Cy7 Ⅱ期临床 NCT03113825 KAI Pharmaceuticals KAI- 9083 细胞穿膜肽 TAT 心肌梗死 εPKC抑制剂 Ⅱ期临床 NCT00093197 KAI Pharmaceuticals KAI- 1678 细胞穿膜肽 TAT 术后疼痛 εPKC抑制剂 Ⅱ期临床 NCT01015235 海昶生物 WGI-0301 脂质纳米颗粒 阳离子脂质QTsome™ 肝细胞癌 AKT-1抑制剂 Ⅰ期临床 NCT05267899 Avilex Pharma AVLX-144 细胞穿膜肽 TAT 急性缺血性卒中、慢性炎性疼痛、蛛网膜下腔出血 PSD-95
抑制剂Ⅰ期临床 NCT04689035 LPP：脂质多聚复合物（lipid-polymer particle）；RTP004：重组纯化型肉毒毒素A（recombinant purified botulinum toxin type A）；TAT转录激活因子：（trans-activator of transcription）；ACPP：可激活细胞穿膜肽（activatable cell penetrating peptide）；JNK：c-Jun氨基末端激酶（c-Jun N-terminal kinase）；PSD-95：突触后致密物蛋白95（Postsynaptic density protein 95）；Cy5，Cy7：近红外荧光染料；εPKC：ε型蛋白激酶C（epsilon protein kinase C）；AKT-1：蛋白激酶Bα（protein kinase B alpha）
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[1] Vishwakarma M, Agrawal P, Soni S, et al. Cationic nanocarriers: a potential approach for targeting negatively charged cancer cell[J]. Adv Colloid Interface Sci, 2024, 327: 103160. doi: 10.1016/j.cis.2024.103160
[2] Gholap AD, Kapare HS, Pagar S, et al. Exploring modified chitosan-based gene delivery technologies for therapeutic advancements[J]. Int J Biol Macromol, 2024, 260(Pt 2): 129581.
[3] Hu LZ, Li J, Yu C, et al. Research advances of polyethylenimine-based nanosystems for gene delivery[J]. Chin J Hosp Pharm(中国医院药学杂志), 2024, 44(7): 853-858. [4] Shrestha S, Tieu T, Wojnilowicz M, et al. Delivery of miRNAs using porous silicon nanoparticles incorporated into 3D hydrogels enhances MSC osteogenesis by modulation of fatty acid signaling and silicon degradation[J]. Adv Healthc Mater, 2024, 13(20): 2400171. doi: 10.1002/adhm.202400171
[5] Chen Q, Sun MJ, Li YN, et al. Nano-vaccines combining customized in situ anti-PD-L1 depot for enhanced tumor immunotherapy[J]. Nanomedicine, 2023, 53: 102693. doi: 10.1016/j.nano.2023.102693
[6] Zhang HQ, Jiang WX, Song TT, et al. Lipid-polymer nanoparticles mediate compartmentalized delivery of Cas9 and sgRNA for glioblastoma vasculature and immune reprogramming[J]. Adv Sci (Weinh), 2024, 11(32): e2309314. doi: 10.1002/advs.202309314
[7] Wu JM, Jones N, Fayez NAL, et al. Protamine-mediated efficient transcellular and transmucosal delivery of proteins[J]. J Control Release, 2023, 356: 373-385. doi: 10.1016/j.jconrel.2023.03.002
[8] Kang ZY, Liu Q, Zhang ZZ, et al. Arginine-rich polymers with pore-forming capability enable efficient intracellular delivery via direct translocation across cell membrane[J]. Adv Healthc Mater, 2022, 11(14): e2200371. doi: 10.1002/adhm.202200371
[9] Alsaiari SK, Patil S, Alyami M, et al. Endosomal escape and delivery of CRISPR/Cas9 genome editing machinery enabled by nanoscale zeolitic imidazolate framework[J]. J Am Chem Soc, 2018, 140(1): 143-146. doi: 10.1021/jacs.7b11754
[10] Wei XW, Zhang ZR. Research advances in cytotoxicities of cationic nanocarriers as gene delivery systems and the mechanisms thereof[J]. Prog Pharm Sci(药学进展), 2016, 40(4): 243-249. [11] Xu CN, Tian HY, Chen XS. Recent progress in cationic polymeric gene carriers for cancer therapy[J]. Sci China Chem, 2017, 60(3): 319-328. doi: 10.1007/s11426-016-0466-x
[12] Zhou Q, Shao SQ, Wang JQ, et al. Enzyme-activatable polymer-drug conjugate augments tumour penetration and treatment efficacy[J]. Nat Nanotechnol, 2019, 14(8): 799-809. doi: 10.1038/s41565-019-0485-z
[13] Yoshinaga N, Numata K. Rational designs at the forefront of mitochondria-targeted gene delivery: recent progress and future perspectives[J]. ACS Biomater Sci Eng, 2022, 8(2): 348-359. doi: 10.1021/acsbiomaterials.1c01114
[14] Machtakova M, Thérien-Aubin H, Landfester K. Polymer nano-systems for the encapsulation and delivery of active biomacromolecular therapeutic agents[J]. Chem Soc Rev, 2022, 51(1): 128-152. doi: 10.1039/D1CS00686J
[15] Xiao QQ, Zoulikha M, Qiu M, et al. The effects of protein Corona on in vivo fate of nanocarriers[J]. Adv Drug Deliv Rev, 2022, 186: 114356. doi: 10.1016/j.addr.2022.114356
[16] Ding TH, Wu EC, Zhan CY. In vivo delivery process and regulating mechanisms of lipid-based nanomedicines[J]. ActaPharmSin(药学学报), 2023, 58(8): 2283-2291. [17] Zu H, Gao DC. Non-viral vectors in gene therapy: recent development, challenges, and prospects[J]. AAPS J, 2021, 23(4): 78. doi: 10.1208/s12248-021-00608-7
[18] Li YJ, Tian RZ, Xu JY, et al. Recent developments of polymeric delivery systems in gene therapeutics[J]. Polym Chem, 2024, 15(19): 1908-1931. doi: 10.1039/D4PY00124A
[19] Sun QH, Zhou ZX, Qiu NS, et al. Rational design of cancer nanomedicine: nanoproperty integration and synchronization[J]. Adv Mater, 2017, 29(14): 1606628 doi: 10.1002/adma.201606628
[20] Yin JJ, Wang JR, Dong X, et al. Negatively charged polymer-shielded supramolecular nano-micelles with stimuli-responsive property for anticancer drug delivery[J]. Int J Pharm, 2022, 627: 122211. doi: 10.1016/j.ijpharm.2022.122211
[21] Shen T, Guan SL, Gan ZH, et al. Polymeric micelles with uniform surface properties and tunable size and charge: positive charges improve tumor accumulation[J]. Biomacromolecules, 2016, 17(5): 1801-1810. doi: 10.1021/acs.biomac.6b00234
[22] Du QL, Liu Y, Fan MY, et al. PEG length effect of peptide-functional liposome for blood brain barrier (BBB) penetration and brain targeting[J]. J Control Release, 2024, 372: 85-94. doi: 10.1016/j.jconrel.2024.06.005
[23] Rudzinski WE, Palacios A, Ahmed A, et al. Targeted delivery of small interfering RNA to colon cancer cells using chitosan and PEGylated chitosan nanoparticles[J]. Carbohydr Polym, 2016, 147: 323-332. doi: 10.1016/j.carbpol.2016.04.041
[24] Bourquin J, Milosevic A, Hauser D, et al. Biodistribution, clearance, and long-term fate of clinically relevant nanomaterials[J]. Adv Mater, 2018, 30(19): e1704307. doi: 10.1002/adma.201704307
[25] Wu JJ, Liang HY, Li YC, et al. Cationic block copolymer nanoparticles with tunable DNA affinity for treating rheumatoid arthritis[J]. Adv Funct Mater, 2020, 30(27): 2000391. doi: 10.1002/adfm.202000391
[26] Chen YM, Lin SS, Wang L, et al. Reinforcement of the intestinal mucosal barrier via mucus-penetrating PEGylated bacteria[J]. Nat Biomed Eng, 2024, 8(7): 823-841. doi: 10.1038/s41551-024-01224-4
[27] Wang X, Cheng WG, Yang QY, et al. Preliminary investigation on cytotoxicity of fluorinated polymer nanoparticles[J]. J Environ Sci (China), 2018, 69: 217-226. doi: 10.1016/j.jes.2017.10.014
[28] Yuan ZH, Guo XS, Wei MY, et al. Novel fluorinated polycationic delivery of anti-VEGF siRNA for tumor therapy[J]. NPG Asia Mater, 2020, 12: 34. doi: 10.1038/s41427-020-0216-9
[29] Xin JR, Lu X, Cao JM, et al. Fluorinated organic polymers for cancer drug delivery[J]. Adv Mater, 2024, 36(30): e2404645. doi: 10.1002/adma.202404645
[30] Han HB, Xing JK, Chen WQ, et al. Fluorinated polyamidoamine dendrimer-mediated miR-23b delivery for the treatment of experimental rheumatoid arthritis in rats[J]. Nat Commun, 2023, 14(1): 944. doi: 10.1038/s41467-023-36625-7
[31] Zhang HP, Meng CY, Yi XW, et al. Fluorinated lipid nanoparticles for enhancing mRNA delivery efficiency[J]. ACS Nano, 2024, 18(11): 7825-7836. doi: 10.1021/acsnano.3c04507
[32] Zhong L, Liu YY, Xu L, et al. Exploring the relationship of hyaluronic acid molecular weight and active targeting efficiency for designing hyaluronic acid-modified nanoparticles[J]. Asian J Pharm Sci, 2019, 14(5): 521-530.
[33] Guo L, Tang YX, Wang L, et al. Synergetic antibacterial nanoparticles with broad-spectrum for wound healing and lung infection therapy[J]. Adv Funct Mater, 2024, 34(39): 2403188. doi: 10.1002/adfm.202403188
[34] Wang KY, Qi LW, Zhao LY, et al. Degradation of chondroitin sulfate: Mechanism of degradation, influence factors, structure-bioactivity relationship and application[J]. Carbohydr Polym, 2023, 301(Pt B): 120361.
[35] Xu FN, Huang XH, Wang Y, et al. A size-changeable collagenase-modified nanoscavenger for increasing penetration and retention of nanomedicine in deep tumor tissue[J]. Adv Mater, 2020, 32(16): 1906745. doi: 10.1002/adma.201906745
[36] Hoogenboezem EN, Patel SS, Lo JH, et al. Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy[J]. Nat Commun, 2024, 15(1): 1581. doi: 10.1038/s41467-024-45609-0
[37] Wang AH, Yang TT, Fan WW, et al. Protein Corona liposomes achieve efficient oral insulin delivery by overcoming mucus and epithelial barriers[J]. Adv Healthc Mater, 2019, 8(12): e1801123. doi: 10.1002/adhm.201801123
[38] Xie YR, Kim NH, Nadithe V, et al. Targeted delivery of siRNA to activated T cells via transferrin-polyethylenimine (Tf-PEI) as a potential therapy of asthma[J]. J Control Release, 2016, 229: 120-129. doi: 10.1016/j.jconrel.2016.03.029
[39] Kandil R, Baldassi D, Böhlen S, et al. Targeted GATA3 knockdown in activated T cells via pulmonary siRNA delivery as novel therapy for allergic asthma[J]. J Control Release, 2023, 354: 305-315. doi: 10.1016/j.jconrel.2023.01.014
[40] Qin M, Du GS, Sun X. Biomimetic cell-derived nanocarriers for modulating immune responses[J]. Biomater Sci, 2020, 8(2): 530-543.
[41] Xia ZX, Mu WW, Yuan SJ, et al. Cell membrane biomimetic nano-delivery systems for cancer therapy[J]. Pharmaceutics, 2023, 15(12): 2770. doi: 10.3390/pharmaceutics15122770
[42] Ren N, Liang N, Dong MW, et al. Stem cell membrane-encapsulated zeolitic imidazolate framework-8: a targeted nano-platform for osteogenic differentiation[J]. Small, 2022, 18(26): e2202485. doi: 10.1002/smll.202202485
[43] Zhou Y, Liang QJ, Wu XJ, et al. siRNA delivery against myocardial ischemia reperfusion injury mediated by reversibly camouflaged biomimetic nano complexes[J]. Adv Mater, 2023, 35(23): e2210691. doi: 10.1002/adma.202210691
[44] Lu YP, Fan LM, Wang J, et al. Cancer cell membrane-based materials for biomedical applications[J]. Small, 2024, 20(7): e2306540. doi: 10.1002/smll.202306540
[45] Li JM, Zhang J, Gao Y, et al. Targeted siRNA delivery by bioinspired cancer cell membrane-coated nanoparticles with enhanced anti-cancer immunity[J]. Int J Nanomedicine, 2023, 18: 5961-5982. doi: 10.2147/IJN.S429036
[46] Zhu LL, Yu XZ, Cao T, et al. Immune cell membrane-based biomimetic nanomedicine for treating cancer metastasis[J]. Acta Pharm Sin B, 2023, 13(6): 2464-2482. doi: 10.1016/j.apsb.2023.03.004
[47] Yang YF, Zhu HC, Liu DK, et al. A versatile platform for the tumor-targeted intracellular delivery of peptides, proteins, and siRNA[J]. Adv Funct Mater, 2023, 33(30): 2301011. doi: 10.1002/adfm.202301011
[48] Fatima M, Almalki WH, Khan T, et al. Harnessing the power of stimuli-responsive nanoparticles as an effective therapeutic drug delivery system[J]. Adv Mater, 2024, 36(24): 2312939. doi: 10.1002/adma.202312939
[49] Liu XH, He F, Liu M. New opportunities of stimulus-responsive smart nanocarriers in cancer therapy[J]. Nano Mater Sci, 2024. doi: 10.1016/j.nanoms.2024.10.013.
[50] Qin JY, Zhu YB, Zheng DS, et al. pH-sensitive polymeric nanocarriers for antitumor biotherapeutic molecules targeting delivery[J]. Bio Des Manuf, 2021, 4(3): 612-626. doi: 10.1007/s42242-020-00105-4
[51] Liu YH, Si LQ, Jiang YX, et al. Design of pH-responsive nanomaterials based on the tumor microenvironment[J]. Int J Nanomedicine, 2025, 20: 705-721. doi: 10.2147/IJN.S504629
[52] Zhang Y, Kim I, Lu YM, et al. Intelligent poly(l-histidine)-based nanovehicles for controlled drug delivery[J]. J Control Release, 2022, 349: 963-982. doi: 10.1016/j.jconrel.2022.08.005
[53] Sun CM, Shen Y, Tu JS. Advance on the research of cell-penetrating peptides[J]. Chin Pharm J(中国药学杂志), 2013, 48(14): 1143-1147. [54] Yu YL, Zu C, He DS, et al. pH-dependent reversibly activatable cell-penetrating peptides improve the antitumor effect of artemisinin-loaded liposomes[J]. J Colloid Interface Sci, 2021, 586: 391-403. doi: 10.1016/j.jcis.2020.10.103
[55] Tang BQ, Zaro JL, Shen Y, et al. Acid-sensitive hybrid polymeric micelles containing a reversibly activatable cell-penetrating peptide for tumor-specific cytoplasm targeting[J]. J Control Release, 2018, 279: 147-156. doi: 10.1016/j.jconrel.2018.04.016
[56] Yan Y, Zhou L, Sun ZW, et al. Targeted and intracellular delivery of protein therapeutics by a boronated polymer for the treatment of bone tumors[J]. Bioact Mater, 2021, 7: 333-340.
[57] Qu HJ, Chen H, Cheng W, et al. Charge-reversible crosslinked nanoparticle for pro-apoptotic peptide delivery and synergistic photodynamic cancer therapy[J]. Nano Res, 2023, 16(12): 13267-13282. doi: 10.1007/s12274-023-5912-7
[58] Kapalatiya H, Madav Y, Tambe VS, et al. Enzyme-responsive smart nanocarriers for targeted chemotherapy: an overview[J]. Drug Deliv Transl Res, 2022, 12(6): 1293-1305. doi: 10.1007/s13346-021-01020-6
[59] Du YN, Li YN, Li XZ, et al. Sequential enzyme activation of a “pro-staramine” -based nanomedicine to target tumor mitochondria[J]. Adv Funct Mater, 2020, 30(9): 1904697. doi: 10.1002/adfm.201904697
[60] Zhang RN, Shao SQ, Piao Y, et al. Esterase-labile quaternium lipidoid enabling improved mRNA-LNP stability and spleen-selective mRNA transfection[J]. Adv Mater, 2023, 35(46): e2303614. doi: 10.1002/adma.202303614
[61] Yan H, Xu PC, Ma H, et al. Enzyme-triggered transcytosis of drug carrier system for deep penetration into hepatoma tumors[J]. Biomaterials, 2023, 301: 122213. doi: 10.1016/j.biomaterials.2023.122213
[62] Liu WJ, Cao JP, Ma CC, et al. Zinc(II)-Quinoline module and ROS cleavable crosslinker functionalized self-fluorescent siRNA vectors for selective gene silencing of cancer cells[J]. J Control Release, 2024, 366: 366-374. doi: 10.1016/j.jconrel.2023.12.055
[63] Hua P, Yang DL, Chen RE, et al. ROS responsive polyethylenimine-based fluorinated polymers for enhanced transfection efficiency and lower cytotoxicity[J]. Bosn J Basic Med Sci, 2022, 22(4): 593-607.
[64] Gao D, Xu M, Cao Z, et al. Ultrasound-triggered phase-transition cationic nanodroplets for enhanced gene delivery[J]. ACS Appl Mater Interfaces, 2015, 7(24): 13524-13537. doi: 10.1021/acsami.5b02832
[65] Cheng Y, Zou JF, He MY, et al. Spatiotemporally controlled Pseudomonas exotoxin transgene system combined with multifunctional nanoparticles for breast cancer antimetastatic therapy[J]. J Control Release, 2024, 367: 167-183. doi: 10.1016/j.jconrel.2023.08.011
[66] Li BH, Zhao MY, Lai WP, et al. Activatable NIR-II photothermal lipid nanoparticles for improved messenger RNA delivery[J]. Angew Chem Int Ed, 2023, 62(25): e202302676. doi: 10.1002/anie.202302676
[67] Aram E, Sadeghi-Abandansari H, Radmanesh F, et al. Shell-sheddable and charge switchable magnetic nanoparticle as pH-sensitive nanocarrier for targeted drug delivery applications[J]. Polym Adv Technol, 2024, 35(4): e6366. doi: 10.1002/pat.6366
[68] Soares PIP, Romão J, Matos R, et al. Design and engineering of magneto-responsive devices for cancer theranostics: Nano to macro perspective[J]. Prog Mater Sci, 2021, 116: 100742. doi: 10.1016/j.pmatsci.2020.100742
[69] Wei WY, Kang HF, Lian CX, et al. Iron-based magnetic nano complexes for combined chemodynamic and photothermal cancer therapy through enhanced ferroptosis[J]. Biomater Adv, 2025, 166: 214046. doi: 10.1016/j.bioadv.2024.214046
[70] Lin LX, Su KX, Zhang XY, et al. A versatile strategy to transform cationic polymers for efficient and organ-selective mRNA delivery[J]. Angew Chem Int Ed, 2025, 64(17): e202500306. doi: 10.1002/anie.202500306
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