pH-responsive selenium nanoplatform for targeted drug release and immune remodeling in microbiota-associated colorectal cancer.

Fusobacterium nucleatum (F. nucleatum) is implicated in colorectal cancer (CRC) initiation, progression, and resistance to therapy, while conventional antibiotics show poor specificity and disrupt intestinal homeostasis. Here, we present a dual bacteria-tumor elimination strategy using a multifunctional nanoagent, SeNPs@CBT, which integrates antibacterial, antitumor, and tumor-targeting functions. Selenium nanoparticles serve as carriers, coated with chitosan-4-carboxyphenylboronic acid and loaded with caffeic acid phenethyl ester (CAPE) via pH-sensitive borate ester bonds. In the acidic tumor microenvironment, SeNPs@CBT release CAPE to eradicate F. nucleatum and modulate immune responses, while the exposed phenylboronic acid groups enhance tumor recognition and uptake, synergistically inducing apoptosis. In an F. nucleatum-associated CRC mouse model, SeNPs@CBT markedly suppressed tumor growth and exhibited potent synergistic effects in bacterial clearance, tumor cell killing, and immune activation. Mechanistic and transcriptomic analyses revealed induction of cell cycle arrest, mitochondrial dysfunction, and activation of the p53 signaling pathway. Together, SeNPs@CBT, based on the triple synergy of bactericidal, tumoricidal, and immune activation, represents a promising nanomedicine platform for the precise treatment of microbiota-related CRC, particularly F. nucleatum-enriched subtypes.