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

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.