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

Abstract

An injectable, self-healing hydrogel (CMCGel) is engineered via dynamic cross-linking of manganese ions and carboxymethyl chitosan to load chlorella extract. The pH/laser dual-responsive platform with endogenous pH gating and exogenous laser switching enables a programmed “Remove–Remodel–Repair” (3R) strategy. CMCGel achieves remarkable tumor suppression (96.01% in vivo), effectively remodels the antitumor immune microenvironment, and promotes postoperative pancreatic fistula repair through durable sealing and anti-inflammatory effects. An injectable, self-healing hydrogel (CMCGel) is engineered via dynamic cross-linking of manganese ions and carboxymethyl chitosan to load chlorella extract. The pH/laser dual-responsive platform with endogenous pH gating and exogenous laser switching enables a programmed “Remove–Remodel–Repair” (3R) strategy. CMCGel achieves remarkable tumor suppression (96.01% in vivo), effectively remodels the antitumor immune microenvironment, and promotes postoperative pancreatic fistula repair through durable sealing and anti-inflammatory effects. 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 (Mn2+) 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 Mn2+ 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, Mn2+ 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.