Injectable Gene/Fiber‐Plexes Reverse Adipose Niche Senescence via Mito‐TERT Activation by Endogenous Mitochondrial Translocation

Abstract Addressing adipose niche senescence is crucial for preventing obesity‐related aging. Telomerase reverse transcriptase (TERT) is a promising target for gene therapy, but traditional methods lack precision and safety. A novel mitochondrion‐located TERT (mito‐TERT) activating approach is presented by injectable gene/short‐fiber complexes (gene/fiber‐plexes) to safely reverse adipose niche senescence from mitochondrial enhancement. The gene/fiber‐plexes are prepared from polydopamine‐coated short‐fibers to adsorb cationic dendrimers (PAMAM G3, PG3) carrying TERT plasmids and Coenzyme Q10 (CoQ10), termed PG3‐TERT@CoQ10. Upon intraperitoneal injection, the gene/fiber‐plexes adhere to the peritoneum and release PG3‐TERT@CoQ10, precisely targeting the adipose niche. Transient active oxygen scavenging by CoQ10 activates TERT transfection and endogenous mitochondrion translocation sequentially, enhancing mitochondrial function. In vitro and in vivo studies shows that gene/fiber‐plexes effectively targeted visceral adipose tissue, increased mito‐TERT levels and restored mitochondrial function. In an obese mouse model, they restored adipose tissue homeostasis and metabolic stability. RNA sequencing indicated reduced senescence‐related genes and restored cell cycle. This mito‐TERT activation strategy shows great promise for treating premature aging and metabolic diseases linked to adipose tissue senescence.