Dual‐Nanocomplex Delivery of Neoantigen Vaccines and Doxorubicin for Synergistic Chemo‐Immunotherapy against Colorectal Cancer

Abstract Colorectal cancer (CRC) is still an important global health challenge, with limited treatment efficacy. Neoantigen‐based cancer vaccines offer tumor‐specific immune activation but are limited by poor immunogenicity and rapid degradation, while chemotherapeutics like doxorubicin (DOX) suffer from non‐selective toxicity and resistance. To overcome these challenges, a dual‐nanocomplex 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‐assembly method. The optimized HCNPs exhibited a uniform size distribution of ≈180 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‐responsive release and selective tumor uptake via CD44 targeting. In vivo studies in MC‐38 tumor‐bearing mice demonstrated that combination therapy with HCNPs and DNPs significantly inhibited tumor growth, enhanced CD8⁺ IFN‐γ⁺ T cell infiltration, reduced M2 macrophage polarization, and expanded memory T cell populations. ELISPOT and LDH assays confirmed potent CTL‐mediated 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.