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Neoantigen\u2010based cancer vaccines offer tumor\u2010specific immune activation but are limited by poor immunogenicity and rapid degradation, while chemotherapeutics like doxorubicin (DOX) suffer from non\u2010selective toxicity and resistance. To overcome these challenges, a dual\u2010nanocomplex delivery platform is developed that integrates immunotherapy and chemotherapy. The first nanocomplex, HCNPs, is functionalized with the neoantigen peptide Adpgk, CpG oligodeoxynucleotides, and hyaluronic acid (HA) via a simple self\u2010assembly method. The optimized HCNPs exhibited a uniform size distribution of \u2248180 nm and are efficiently internalized by dendritic cells (DCs), promoting DC s maturation. The second nanocomplex, DNPs, formulated with chitosan (CS), HA, and DOX, achieved pH\u2010responsive release and selective tumor uptake via CD44 targeting. In vivo studies in MC\u201038 tumor\u2010bearing mice demonstrated that combination therapy with HCNPs and DNPs significantly inhibited tumor growth, enhanced CD8\u207a IFN\u2010\u03b3\u207a T cell infiltration, reduced M2 macrophage polarization, and expanded memory T cell populations. ELISPOT and LDH assays confirmed potent CTL\u2010mediated cytotoxicity. Importantly, no significant toxicity was observed. The results established a safe and effective nanoplatform that synergistically combines immune activation and targeted delivery, offering a promising strategy for improving CRC immunochemotherapy.<\/jats:p>","DOI":"10.1002\/adhm.202503947","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T10:35:59Z","timestamp":1762770959000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dual\u2010Nanocomplex Delivery of Neoantigen Vaccines and Doxorubicin for Synergistic Chemo\u2010Immunotherapy against Colorectal Cancer"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3236-8892","authenticated-orcid":false,"given":"Weijian","family":"Zhao","sequence":"first","affiliation":[{"name":"College of Chemistry &amp; Life Science Beijing University of Technology  NO. 100, Pingleyuan, Chaoyang Beijing 100124 P. R. 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