Sprayed Hyaluronic Acid Based Multidrug Composite Hydrogel for Postoperative Colorectal Cancer Ultra-Efficient Long-Lasting Multi-Stage Immuno-Chemo Synergistic Therapy

To enhance the therapeutic efficacy of postoperative colorectal cancer treatment and prevent peritoneal metastasis, we propose a strategy utilizing the photothermal-induced ultra-efficient and long-lasting multi-stage immuno-chemo synergistic therapy. To implement this strategy, oxaliplatin (OXA), curcumin (Cur), and Mn2+ were coordinated to form infinite coordination polymer nanoparticles (OXA-Mn(II)-Cur ICP NPs). These nanoparticles are encapsulated with polydopamine (PDA) to create OXA-Mn(II)-Cur ICP@PDA NPs, which are subsequently embedded in a sprayable hyaluronic acid-based hydrogel. The resulting ICP@PDA NPs@composite hydrogel exhibits strong tissue adhesion and segmented pH-responsive drug release properties. Notably, the hydrogel can sustainably release drugs for over 20 days in vivo, maximizing local drug concentration while minimizing systemic toxic side effects. Each component of the composite hydrogel serves multiple functions, and its application to postoperative tumor sites enables long-term, dual-pathway, multi-stage immune activation. This immune response synergizes with chemotherapy to achieve a highly effective therapeutic outcome. In vivo experiments demonstrated that the composite hydrogel effectively eliminates residual tumors, ensuring a 100% survival rate without recurrence for 80 days in treated mice. Furthermore, it inhibits peritoneal metastasis and completely eradicates intraperitoneal tumors within 20 days. The ICP@PDA NPs@composite hydrogel represents a promising therapeutic platform for postoperative colorectal cancer treatment and metastasis prevention.