Reprogramming immunological debris clearance with astaxanthin-loaded engineered probiotic vesicles suppresses colorectal tumorigenesis.

Inefficient clearance of tumor-associated cellular debris sustains chronic inflammation and reinforces tumor-promoting immune niches in the colorectal cancer (CRC), yet strategies to selectively enhance macrophage-mediated cellular debris clearance remain largely unexplored. Here, we engineered a dual-targeted oral nanoplatform based on probiotic-derived extracellular vesicles (EVs) for selective delivery of astaxanthin (AXT-EVs) to tumor-associated macrophages (TAMs) in inflamed colonic tissues. Following oral administration, AXT-EVs preferentially accumulated within TAMs and induced functional reprogramming toward enhanced inflammatory debris resolution. Internalized AXT downregulates bridging integrin 2 (BIN2), a previously unrecognized negative regulator of macrophage phagocytic remodeling, thereby restoring macrophage-mediated clearance of tumor-associated cellular debris and disrupting debris-driven inflammatory amplification. In murine CRC models, AXT-EVs significantly inhibited tumor progression, alleviated intestinal inflammation and restored epithelial barrier integrity. Our findings identify defective macrophage debris clearance as a therapeutically targetable driver of colorectal tumorigenesis and establish a probiotic nanovesicle-based strategy as an immune-modulating platform for restoring tissue clearance homeostasis.