PGC1α-Inducing Senomorphic Nanotherapeutics Functionalized with NKG2D-Overexpressing Cell Membranes for Intervertebral Disc Degeneration.
Sheng LiuKanglu LiYuxin HeSheng ChenWenbo YangXuanzuo ChenShiqing FengLiming XiongYizhong PengZeng-Wu ShaoPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
Cellular senescence is a significant contributor to intervertebral disc aging and degeneration. However, the application of senotherapies, such as senomorphics targeting senescence markers and the senescence-associated secretory phenotype (SASP), remains limited due to challenges in precise delivery. Given that the natural killer group 2D (NKG2D) ligands are increased on the surface of senescent nucleus pulposus (NP) cells, the NKG2D-overexpressing NP cell membranes (NNPm) are constructed, which is expected to achieve a dual targeting effect toward senescent NP cells based on homologous membrane fusion and the NKG2D-mediated immunosurveillance mechanism. Then, mesoporous silica nanoparticles carrying a peroxisome proliferator-activated receptor-ɣ coactivator 1α (PGC1α)inducer (SP) are coated with NNPm (SP@NNPm) and it is found that SP@NNPm selectively targets senescent NP cells, and the SP cores exhibit pH-responsive drug release. Moreover, SP@NNPm effectively induces PGC1α-mediated mitochondrial biogenesis and mitigates senescence-associated markers induced by oxidative stress and the SASP, thereby alleviating puncture-induced senescence and disc degeneration. This dual-targeting nanotherapeutic system represents a novel approach to delivery senomorphics for disc degeneration treatment.
Keyphrases
- induced apoptosis
- dna damage
- oxidative stress
- cell cycle arrest
- endothelial cells
- skeletal muscle
- nk cells
- stress induced
- endoplasmic reticulum stress
- natural killer cells
- diabetic rats
- signaling pathway
- cancer therapy
- cell therapy
- cell death
- high resolution
- mass spectrometry
- binding protein
- ultrasound guided
- drug induced
- replacement therapy