Noninvasive cardiac modulation via triplet-sensitized photoswitching in the phototherapeutic window

Red, far red, or near-infrared photoswitchable drugs offer immense photo-pharmacological advantages due to the higher light penetration through the skin. Such photoactivation is achieved using processes such as two- and three-photon absorption, excited-state absorption, and triplet-triplet annihilation upconversion, which require higher photon fluences (W to kW cm^-2) than the resilience constraints of skin (200 mW cm^-2). Herein, a generalized approach of cis-to-trans photoisomerization of azobenzenes is demonstrated via triplet sensitization with NIR-I illumination (850 nm) of a new Zn-octa-substituted phthalocyanine photosensitizer, in aqueous medium at 2.62 mW cm^-2. The approach is applied to control the heart rate of a frog tadpole via cis-to-trans photoisomerization of an azobenzene-functionalized muscarinic acetylcholine receptor M₂ agonist in the phototherapeutic window (730 nm excitation: 42 mW cm^-2). This advance highlights a powerful photo-pharmacological strategy for modulation of in vivo activity at 2-4 orders of magnitude lower photon fluences of NIR light compared to established methods.