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To address this efficacy-toxicity trade-off, we present a charge-mixed nanogel platform that reconciles high delivery potency with excellent biocompatibility. Specifically, a library of cationic nanogels was synthesized with precise control over charge composition, size, and cross-linking degree, enabling systematic investigation of their effects on delivery performance and toxicity. Our findings reveal that delivery efficiency is cooperatively modulated by charge, size, and cross-linking degree, whereas toxicity reduction is primarily achieved by diluting the positive charge density through incorporation of anionic units. The established structure-activity relationship identified an optimal formulation comprising 80% cationic and 20% anionic monomers, with a hydrodynamic radius of approximately 83 nm and a cross-linking degree of 20% using a disulfide-based cross-linker. This design enables intracellular glutathione-responsive dissociation and efficient siRNA release. The engineered charge-mixed nanogels demonstrate potent gene silencing (83.0%) and antitumor efficacy (84.3%), alongside notably reduced cellular and systemic toxicity. Collectively, this work provides rational design principles for cationic nanocarriers and establishes a promising vector platform that effectively overcomes the efficacy-toxicity dilemma for advanced siRNA therapeutics.<\/jats:p>","DOI":"10.1021\/acsami.6c17668","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T19:01:54Z","timestamp":1788894114000},"page":"50663-50680","source":"Crossref","is-referenced-by-count":0,"title":["Charge-Mixed Nanogels for siRNA Delivery: Concurrent Optimization of Efficacy and Safety via Structure\u2013Activity Relationships"],"prefix":"10.1021","volume":"18","author":[{"given":"Yifan","family":"Gao","sequence":"first","affiliation":[{"name":"East China University of Science and Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingying","family":"Fang","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuening","family":"Qiu","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilei","family":"Yu","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Du","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martien A.","family":"Cohen Stuart","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4693-850X","authenticated-orcid":true,"given":"Junyou","family":"Wang","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Gao","sequence":"additional","affiliation":[{"name":"Changzheng hospital, Second Affiliated Hospital of Second Military Medical University , , 415 Fengyang road , ,","place":["Shanghai, People\u2019s Republic of China, 200003"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"2026100820080895600_cit1","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.addr.2016.06.011","article-title":"Recent progress in development of siRNA delivery vehicles for cancer therapy","volume":"104","author":"Kim","year":"2016","journal-title":"Adv. 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