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We fabricated dual-responsive and tumor-targeting nucleic acid base-inspired nanogels (DTNANGs) for the in vivo codelivery of gemcitabine (Gem) and cytochrome C (CC). The nanogels were engineered through pH-sensitive base-pairing cross-linking between guanine- and cytosine-modified hyaluronic acid derivatives. DTNANGs achieved high drug-loading efficiency (96.3% for Gem, 94.5% for CC). In vitro and in vivo experiments confirmed that DTNANGs demonstrated superior CD44-mediated tumor-targeting capacity, enhanced tumor accumulation, improved cellular uptake, and fast endolysosomal escape. Additionally, CC-loaded DTNANGs increased cell apoptosis by 75.5% in A549 cells, outperforming monotherapy. Moreover, in vivo evaluations in A549 tumor-bearing mice revealed that they significantly inhibited tumor growth (70% inhibitory rate) compared to other control groups, while exhibiting negligible systemic toxicity. Our study lays the groundwork for controlled, effective codelivery of chemo- and protein drugs, enabling precision cancer therapy.<\/jats:p>","DOI":"10.1021\/acs.biomac.5c01632","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T20:11:19Z","timestamp":1758226279000},"page":"7177-7189","source":"Crossref","is-referenced-by-count":4,"title":["Bioresponsive\nNucleic Acid Base Pair-Inspired Nanogels\nfor Codelivery of Chemo-\/Protein Drugs in Targeted Cancer Therapy"],"prefix":"10.1021","volume":"26","author":[{"given":"Yan","family":"Fu","sequence":"first","affiliation":[{"name":"Jilin Institute of Chemical Technology , , ,","place":["Jilin City, Jilin Province, P. R. China, 132022"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Jilin Institute of Chemical Technology , , ,","place":["Jilin City, Jilin Province, P. R. 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