NIR-Activated Enteric Prodrug Microparticles for Bioimaging-Guided Chemotherapy of Colorectal Cancer

Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide. 5-Fluorouracil (5-FU) is a first-line chemotherapeutic widely used in CRC treatment, but its systemic administration often causes severe toxicity due to uncontrolled biodistribution. Herein, we present near-infrared (NIR)-activated enteric prodrug microparticles, HPMCP@L-UCNPs-ONB-5-FU, which enable spatiotemporally controlled release of 5-FU in the colon. The photocleavable prodrug o-nitrobenzyl-5-fluorouracil (ONB-5-FU) is conjugated to large upconversion nanoparticles (L-UCNPs) and encapsulated within the enteric polymer hydroxypropyl methylcellulose phthalate (HPMCP) to resist gastric degradation. After oral administration, low-power 980 nm excitation yields 800 nm emission for bioimaging, whereas high-power excitation generates strong 365 nm emission that cleaves the ONB linker and locally releases active 5-FU. In vitro studies confirmed light-gated and power-dependent drug release, while cellular and orthotopic CRC studies demonstrated potent tumor inhibition with minimal systemic toxicity. Overall, this work establishes a precise and biocompatible NIR-controlled prodrug activation paradigm for oral chemotherapy of CRC.