Abstract

Achilles tendinopathy represents a prototypical musculoskeletal disorder driven by a self-perpetuating “inflammaging” vicious cycle, where chronic inflammation and stem cell senescence mutually reinforce to precipitate tissue failure. Current therapeutics inadequately address the complex intercellular signaling fueling this loop. Herein, we present a reactive oxygen species (ROS)-responsive photothermal cascade nanoplatform (LT-NPs) that couples Licochalcone A delivery with mild near-infrared (NIR) hyperthermia (∼42 °C). Unlike conventional ablative therapies, this platform leverages mild thermal stress as a safe, generalized immunometabolic modulator. Mechanistically, we identify the mitochondrial DNA (mtDNA)-cGAS-STING axis as the pivotal “bridge” connecting mitochondrial dysfunction to immune dysregulation. The LT-NPs-NIR system dismantles this pathology via a synergistic “dual-lock” strategy: (1) mild photothermal heating induces heat shock protein 70 (HSP70) to seal mtDNA leakage; and (2) released Licochalcone A directly inhibits the downstream STING sensor. Crucially, this intervention re-engineers the dysregulated crosstalk between the immune niche and tendon stroma: by reprogramming M1 macrophages toward a reparative M2 phenotype and simultaneously rescuing tendon stem/progenitor cells (TSPCs) from senescence-associated secretory phenotype (SASP)-mediated senescence, the platform effectively uncouples the reciprocal feedback loop between inflammation and degeneration. In vivo, this orchestrated restoration of the microenvironment significantly suppresses heterotopic ossification and recovers biomechanical function. Consequently, the “mild photothermal cascade” concept establishes a versatile therapeutic paradigm, offering a scalable strategy to resolve the intricate inflammation-senescence crosstalk across a broad spectrum of age-related pathologies.