A Mitochondrial Autophagy‐Synthesis Dynamic Equilibrium Liposome for the Repair of Energy Metabolism in Acute Kidney Injury

Acute kidney injury (AKI) is a clinical syndrome primarily attributed to mitochondrial dysfunction, characterized by disrupted mitochondrial balance. Impaired biogenesis leads to insufficient energy supply, while defective autophagy results in the accumulation of damaged mitochondria-both of which exacerbate injury to renal tubular epithelial cells. In this study, we developed melatonin/pioglitazone liposomes (MP@Lip) for AKI therapy via restoration of mitochondrial dynamic balance. When melatonin and pioglitazone was jointly delivered to damaged renal tubules, they activated mitochondrial autophagy and biogenesis, thereby bidirectionally restoring mitochondrial network homeostasis. Mechanistically, AMPK/SIRT3/PGC-1α-related signaling may be involved in the mitochondrial protection of MP@Lip. Upon AMPK phosphorylation, SIRT1/SIRT3 deacetylase activity is upregulated, the ratio of LC3B-II/LC3B-I increases, p62/SQSTM1 decreases, and autophagy is enhanced. PGC-1α enhances transcriptional activity and promotes the expression of mitochondrial biogenic markers (TOM20). This complementary degradation-synthesis loop gradually restores mitochondrial dynamic balance. In vitro experiments confirmed that MP@Lip reduces ROS production and apoptosis while restoring mitochondrial membrane potential. In vivo studies demonstrated improvement in renal function indicators, alleviation of inflammatory responses and histopathological damage, and no systemic toxicity. This strategy shifts AKI treatment from symptomatic support to ameliorating mitochondrial dysfunction, providing a targeted, complementary and relatively safe approach that may be applicable to other mitochondrial functional-related diseases.