Biomimetic HCT116 membrane-cloaked nanoplatform for potentiated chemo-immunotherapy of colorectal cancer: Homologous targeting and immunogenic microenvironment remodeling

Background Oxaliplatin (OXP) resistance and an immunosuppressive microenvironment are major hurdles in colorectal cancer (CRC) treatment. This study developed a biomimetic "Trojan Horse" nanoplatform (CCM@CONPs) to systematically elucidate its therapeutic efficacy and mechanisms in overcoming these barriers. Methods A biomimetic delivery system was engineered by cloaking OXP/Celecoxib (CXB)-loaded methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) micelles with HCT116 cancer cell membranes. Physicochemical characterization and homologous targeting capabilities were assessed. The synergistic molecular mechanisms regarding cyclooxygenase-2 (COX-2) inhibition, DNA damage, immunogenic cell death (ICD), and subsequent pro-inflammatory cytokines secretion were investigated in vitro. In vivo anti-tumor efficacy, immune activation profiles, and biosafety were evaluated in CRC xenograft models. Results The study successfully fabricated CCM@CONPs with a uniform core-shell structure and excellent stability. The biomimetic coating conferred precise homologous targeting, resulting in significantly enhanced cellular uptake compared to non-coated micelles. Mechanistically, co-delivered CXB functioned as a sensitizer by abrogating the COX-2 signaling axis, which potentiated OXP-mediated genotoxicity and downregulated DNA repair mechanisms. This precise "seek-and-destroy" strategy amplified OXP-induced ICD and significantly stimulated the secretion of pro-inflammatory cytokines (such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ)) in vitro, indicating its robust potential to alleviate local immunosuppression. In vivo evaluations further demonstrated that CCM@CONPs achieved superior tumor growth inhibition with negligible systemic toxicity. Conclusion This study suggests that CCM@CONPs exerts potent anti-cancer effects in CRC via active homologous targeting and mechanism-based molecular sensitization. By effectively mitigating tumor defense networks and promoting pro-inflammatory immune responses, this bio-inspired platform provides a highly translational and valuable framework for advancing precision chemo-immunotherapy in refractory CRC.