On-demand mild photothermal cascade platform reprogramming mitochondrial immunity for tendon rejuvenation

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Immunology

Background:

• Achilles tendinopathy involves chronic inflammation and stem cell senescence, creating a self-perpetuating cycle of tissue damage.
• Existing treatments fail to address the complex signaling pathways driving this
• inflammaging
• cycle.
• Mitochondrial dysfunction and immune dysregulation are key factors in tendinopathy pathogenesis.

Purpose of the Study:

• To develop a reactive oxygen species (ROS)-responsive nanoplatform (LT-NPs) for treating Achilles tendinopathy.
• To investigate the mechanism of mild photothermal hyperthermia combined with Licochalcone A delivery.
• To evaluate the therapeutic potential of targeting the mitochondrial DNA (mtDNA)-cGAS-STING axis.

Main Methods:

• Fabrication of LT-NPs encapsulating Licochalcone A, designed for ROS-triggered release and photothermal conversion.
• Application of mild near-infrared (NIR) hyperthermia (∼42°C) to activate LT-NPs.
• Assessment of the nanoplatform's effect on the mtDNA-cGAS-STING pathway, macrophage polarization, and tendon stem/progenitor cell (TSPC) senescence.
• In vivo evaluation of heterotopic ossification suppression and biomechanical function recovery in a tendinopathy model.

Main Results:

• The LT-NPs-NIR system effectively inhibited the mtDNA-cGAS-STING axis, a key mediator of inflammation.
• Mild hyperthermia induced heat shock protein 70 (HSP70), preventing mtDNA leakage, while Licochalcone A blocked STING.
• The treatment reprogrammed M1 macrophages to M2 phenotype and rescued TSPCs from senescence-associated secretory phenotype (SASP).
• In vivo studies demonstrated significant suppression of heterotopic ossification and improved biomechanical properties.

Conclusions:

• The developed LT-NPs-NIR system offers a synergistic "dual-lock" strategy to disrupt the inflammation-senescence crosstalk in Achilles tendinopathy.
• Mild photothermal cascade therapy represents a versatile and scalable approach for treating age-related pathologies.
• This approach effectively restores the microenvironment, promoting tendon healing and function.