Self‐Fueling Nanobacteria Harnesses Leaked Pancreatic Fluid to Eradicate Residual Tumors After Surgery

Postoperative management of pancreatic ductal adenocarcinoma (PDAC) remains hindered by two closely linked challenges: the harmful effects of pancreatic fistula and the high risk of local tumor recurrence. Although leaked pancreatic fluid (PF) is generally regarded as a postoperative complication, its abundance of digestive enzymes also suggests an underexplored therapeutic opportunity. Here, we developed a localized therapeutic strategy that converts the enzyme-rich fistula microenvironment from a pathological burden into an antitumor resource. To achieve this, we nano-engineered Bacteroides thetaiotaomicron (B.t.) and integrated it with TRPV1 antagonist-loaded nanomicelles in a GelMA hydrogel, generating the platform TNPs-N@B.t. + Gel. Mechanistically, this system acts in a coordinated manner within the postoperative PDAC microenvironment. B.t. degrades tumor-associated mucins, thereby dismantling the protective barrier that shields PDAC cells from pancreatic enzymes and restoring their vulnerability to enzymatic attack. Meanwhile, PF forms an in situ digestive enzyme corona on the nanoengineered bacterial surface, which promotes deeper tumor penetration by disrupting intercellular adhesion. In parallel, delivery of the TRPV1 antagonist (TRPV1a) suppresses CGRP release, attenuates cancer-associated fibroblast (CAF) activation, and facilitates NK-cell-associated antitumor responses. In postoperative PDAC models, TNPs-N@B.t. + Gel showed durable local retention, enhanced tumor accumulation, suppressed recurrence, prolonged survival, and alleviated pain-related behaviors without evident systemic toxicity.