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 <i>in vivo</i>, 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. <i>In vivo</i> 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.