Breaking Bonds with Short-Wave Infrared Light: BODIPY Photocages for Two-Photon Activation in the 900-1500 nm NIR-II Window.

Photocages enable light-triggered cargo release in biological systems, but their excitation is often restricted to UV/visible wavelengths, where tissue penetration is limited. Two-photon excitation (2PE) offers a solution by allowing near-infrared (NIR) or short-wave infrared (SWIR) activation within biological windows of maximal tissue transparency. While photocaging in the first biological window (650-950 nm) has been demonstrated, applications in the second biological window (1000-1350 nm) remain unexplored. Here, we investigate the two-photon absorption (2PA) properties of 11 BODIPY photocages featuring single-photon absorption spanning 450-750 nm, focusing on 3- and 5-position substitutions to identify key motifs that enhance 2PA in the 900-1500 nm range. We find that strong charge transfer character and increased vibrational freedom can relax symmetry-related selection rules, significantly enhancing 2PA. Cross sections (δ) exceeded 4000 GM at 900 nm for a bis(styryl)-BODIPY with carbazole units and reached 1110 GM at 1240 nm for its monostyryl analog. Two additional B-methylated molecules with improved uncaging quantum yields were synthesized, yielding uncaging action cross sections (δΦ) up to 5.8 GM at 900 nm and around 1 GM at 1300-1400 nm. Notably, these modifications preserve the core photophysical properties of BODIPY, making them ideal for molecular engineering. These findings highlight key design principles for efficient 2P-activatable photoactuators operating in the NIR-II biological window and show that heterolytic C-O bond cleavage can be triggered by two SWIR photons carrying as little as 20 kcal/mol each.