A Manganese-Chlorella Hydrogel for an Integrated “Remove–Remodel–Repair” Strategy in Pancreatic Cancer Therapy

Abstract Pancreatic cancer faces the challenges of tumor progression and postoperative pancreatic fistula during the perioperative period, which severely affect patient prognosis. In this study, an injectable self-healing multifunctional hydrogel (CMCGel) was developed based on dynamic cross‑linking between manganese ions (Mn 2+ ) and carboxymethyl chitosan loaded with chlorella extract (CE). This platform implements an integrated “Remove – Remodel – Repair” (3R) strategy for comprehensive perioperative management. CMCGel exhibits distinctive pH/laser dual-responsive behavior: In the acidic tumor microenvironment, the accelerated release of CE and Mn 2+ enhances photodynamic therapy and chemodynamic therapy (CDT). This combination, activated by laser and gated by endogenous pH, achieves remarkable tumor suppression rates of 85.81% in vitro and 96.01% in vivo. As pH normalizes, Mn 2+ shifts from CDT to activate the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway, remodeling the immune microenvironment. Crucially, CMCGel’s adhesion strength in artificial pancreatic fluid at 48 h was 4703.80 ± 50.36 Pa, only 8.17% lower than that at 10 min. This enzyme-resistant property enables durable mechanical sealing at the fistula site, reducing amylase leakage by 55.71% and creating favorable conditions for tissue repair. By integrating pH/laser-triggered combination therapy, immunomodulation, and enzyme-resistant barrier functionality into a single platform, CMCGel presents a clinically promising strategy for perioperative management of pancreatic cancer.