Mitochondria-targeted phototherapeutic system enabling spatiotemporal-controlled NADH depletion for keloid intervention.

Keloids represent a fibroproliferative disorder characterized by excessive collagen deposition and dysregulated cellular metabolism, yet effective therapeutic strategies remain limited due to the lack of precise intervention at the subcellular level. Herein, we report a mitochondria-targeted phototherapeutic system (TBQQPt) that enables spatiotemporal-controlled metabolic disruption through light-triggered NADH depletion. Unlike conventional photosensitizers that primarily rely on reactive oxygen species (ROS) generation, TBQQPt integrates mitochondrial localization with redox intervention, allowing localized consumption of NADH and amplification of oxidative stress within mitochondria. Mechanistically, TBQQPt accumulates in mitochondria and, upon light irradiation, induces efficient NADH oxidation, leading to mitochondrial dysfunction, enhanced ROS generation, and subsequent fibroblast inactivation. This dual mechanism establishes a self-amplifying therapeutic cascade that disrupts cellular energy metabolism and redox homeostasis. In vitro studies demonstrate significant inhibition of fibroblast proliferation and collagen production. In vivo, TBQQPt-mediated phototherapy effectively suppresses keloid progression with minimal off-target toxicity, as further supported by transcriptomic analysis revealing downregulation of fibrosis- and metabolism-related pathways. Overall, this work provides a subcellularly targeted and spatiotemporally controllable strategy for keloid treatment, highlighting the potential of integrating drug delivery with metabolic intervention for precision therapy of fibrotic diseases.