Spatiotemporal Activation of a Quercetin-Based Prodrug via Two-Photon Excitation of Its Intrinsic ESIPT Chromophore

The precise and spatiotemporally confined activation of therapeutic agents in living tissue remains a major challenge in drug delivery. Existing photopharmacological systems suffer from poor tissue penetration, phototoxicity, and the scarcity of biocompatible chromophores with robust nonlinear optical response. Here we introduce and theoretically validate a natural, biocompatible platform for two-photon drug activation based on quercetin’s intrinsic excited-state intramolecular proton-transfer (ESIPT) chromophore. Using a fully quantum-mechanical framework, we simulate the ultrafast cascade triggered by simultaneous absorption of two NIR photons, which promotes quercetin to its first excited state. Within tens of femtoseconds, the nuclear wavepacket undergoes ESIPT, forming a high-energy keto tautomer that dramatically reshapes the potential-energy surface along the linker coordinate. This electronic reorganization lowers the bond-dissociation barrier by ~ 68% and elongates the equilibrium bond length by ~ 38%, funnelling the system into a barrierless dissociative channel. Time-dependent Schrödinger equation simulations reveal sub-100-fs proton-transfer kinetics, picosecond-scale bond rupture, and an overall cleavage yield exceeding 80%. The mechanism is further validated by a pronounced kinetic isotope effect (KIE ≈ 3.2) and strong spectral selectivity, with optimal activation centered at 800 nm. By integrating natural ESIPT reactivity, two-photon nonlinear optics, and prodrug chemistry, this work establishes a theoretical foundation for a new class of biocompatible, quantum-controlled phototherapeutics capable of deep-tissue activation with unprecedented spatiotemporal precision, bridging a longstanding gap between molecular photophysics and precision medicine.