Near-Infrared Upconversion Modulation of Intracellular Protons for Autophagy-Induced Apoptosis

Protons critically regulate cancer cell behavior, metabolism, and signaling pathways, making intracellular pH modulation a promising therapeutic strategy. Yet, precise spatiotemporal control of proton levels remains a formidable challenge. In this study, we introduce a near-infrared (NIR)-controlled nanoscale proton delivery system using upconversion nanoparticles (UCNPs) coated with photoacid (PA) and ferrocene (Fc). Upon 980 nm NIR stimulation, UCNPs emit UV-visible emission (300-500 nm), activating surface-bound PA to induce transient H⁺ release and acidify the tumor microenvironment in vivo. This acute acidic stress reduces tumor cell glucose uptake by 50% and suppresses mechanistic target of rapamycin (mTOR) signaling, triggering excessive autophagy that functionally drives mitochondrial dysfunction and intrinsic apoptosis-a process we define as proton-mediated autophagy-induced apoptosis (PAA). Fc, a biodegradable peroxidase mimic and a non-fluorescent quencher, is incorporated to enable real-time visual quantification of proton accumulation via H⁺-triggered biodegradation, restoring the NIR upconversion luminescence (at 800 nm) of UCNPs. Following intravenous administration, the nanoagent achieves a six-fold reduction in tumor weight and elevates proton levels in glioma, effectively triggering PAA under non-invasive NIR irradiation. This work establishes a spatiotemporally controlled platform for intratumoral proton dynamics, enabling precision cancer theranostics.