Modular One-Pot Access to Boron-Carboxylated Dipyrromethene Dyes as Visible-Light and Two-Photon Activatable Photocages

The photocage, an advanced platform for drug delivery and photoactivation imaging, has attracted wide attention in biomedicine. Despite recent advancements in shifting irradiation wavelengths to visible and near-infrared light, improving photolysis quantum yield and the corresponding uncaging cross section, key parameters for efficient photocages, remains highly challenging. Here, we address this challenge by introducing light-controlled COO-B bond cleavage from tetracoordinate boron linked to dipyrrin, aryl, and carboxylic acid groups. We developed a multicomponent diversity-oriented one-pot method to streamline the synthesis of BODIPY-cages, enabling the creation of a diverse library of photocages for systematic investigation of their photorelease structure-activity relationships and mechanisms. Thanks to efficient COO-B bond photolysis and the impressive extinction coefficients of BODIPYs, the developed photocages possess uncaging cross sections up to 1488 M^-1 cm^-1, enabling rapid lysosome photoactivation fluorescence imaging at low light and dye doses (0.2 mW, 50 nM) and sequential two-photon (λ_ex = 950 nm) photoactivation in zebrafish. When loaded with the drug valproic acid (VPA), these photocages optimize drug uptake and achieve precise photoactivation release in the endoplasmic reticulum or lysosomes, boosting drug efficacy ∼18,540-fold. Our one-pot accessed photocages, with impressive uncaging cross sections, two-photon activation capability, and photoactivatable fluorescence imaging and drug release abilities, provide a valuable paradigm for developing multifunctional photoactivation platform. We expect our study to break new ground in the construction of tetracoordinate boron photocages with diverse structures and functions.