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

In this study, we introduce a transformative strategy for noninvasive modulation of biological activity using light that penetrates living tissue deeply and safely. Traditional photoswitchable drugs, particularly those based on azobenzene, are activated by ultraviolet or blue light, which suffer from poor tissue penetration and require high photon fluence, limiting their applicability in vivo. Our work overcomes these constraints by exploiting triplet-sensitized photoisomerization to shift the activation spectrum of azobenzene derivatives into the far-red (FAR) and near-infrared (NIR) phototherapeutic window (730–850 nm), where light penetrates more profoundly and with reduced photodamage.We designed a  photosensitizer capable of efficient triplet energy transfer under low-intensity near infrared light illumination (850 nm, ~2.6 mW cm⁻²), orders of magnitude lower than conventional multiphoton or upconversion-based methods. This enabled cis-to-trans photoisomerization of azobenzene derivatives in aqueous media, demonstrating robust photoswitching under biologically relevant light intensities.Importantly, we translated this mechanism into a biological application: by pairing the photosensitizer with an azobenzene-functionalized muscarinic acetylcholine receptor M₂ agonist, we achieved light-controlled modulation of heart rate in frog tadpoles in vivo, using excitation at 730 nm within safety limits compatible with human skin. This provides a proof-of-concept for deep-tissue photopharmacology with potential applications spanning cardiology, neuromodulation, and precision therapeutics.Our approach demonstrates that triplet-sensitized photoswitching can operate 2–4 orders of magnitude below the photon fluences required by alternative photoactivation strategies, greatly expanding the practical utility of photoswitchable drugs. Beyond cardiac modulation, this work lays foundational groundwork for safe, noninvasive, light-activated therapies in complex organisms, heralding a new class of photopharmacological tools that marry photophysics with biomedical function.