Microenvironment-Responsive Nanomaterials for Colorectal Anastomotic Healing: A Signal-Threshold-Response Framework for Stage-Adaptive Repair.

Colorectal anastomotic leakage remains a major source of morbidity and mortality after intestinal reconstruction. Many current sealants, hydrogels, nanocomposites, and local nanomedicine platforms are optimized for static mechanical support, tissue adhesion, or sustained release, whereas the anastomotic wound evolves through temporally coupled changes in perfusion, redox state, protease activity, pH, and microbial activity. This review evaluates stimuli-responsive nanomaterials through an anastomosis-specific signal-threshold-response framework. Evidence is separated into direct preclinical studies performed in colorectal or colonic anastomosis models and transferable mechanistic or proof-of-concept evidence derived from gastrointestinal and other non-anastomotic tissue-repair models. We first synthesize available evidence on the spatial distribution, postoperative dynamics, and pathophysiological roles of anastomosis-relevant cues. We then evaluate pH-, reactive oxygen species-, enzyme-, hypoxia-, microbial-, and multi-input-responsive systems according to their sensing mechanisms, reported activation conditions, material transformations, therapeutic outputs, and levels of evidence. We further propose design principles for matching response kinetics and mechanical evolution to the inflammatory, proliferative, and remodeling phases. Future development should prioritize quantitative mapping of local cues, logic-gated or sequential activation, wet-tissue mechanics, microbiota-preserving antimicrobial action, and validation in clinically relevant large-animal models. This framework positions responsive nanomaterials as stage-adaptive adjuncts rather than generic drug-delivery systems for colorectal anastomotic repair.