Renal-targeted tFNA-TPP nanoagonist treats acute kidney injury by amplifying mitophagy.

Acute kidney injury (AKI) is a critical clinical syndrome closely associated with mitochondrial dysfunction. Its etiology encompasses both intrinsic renal factors and extrarenal factors, such as cardiac complications following heart surgery. AKI remains a formidable therapeutic challenge due to the absence of strategies capable of precisely targeting and reversing mitochondrial dysfunction, a key pathological driver. To address this, we developed a renal-targeted mitochondrial autophagy inducer, tFNA-TPP, by covalently linking tetrahedral framework nucleic acid (tFNA) with triphenylphosphine (TPP) using click chemistry. This nanocomposite demonstrates a 91.6% efficiency in targeting the kidneys and functions as an integrated system for ROS scavenging and mitophagy activation. The tFNA component promotes renal accumulation and neutralizes reactive oxygen species, while the TPP moiety ensures precise delivery to damaged mitochondria, enhancing organelle-specific autophagy. In AKI models induced by both cisplatin and ischemia-reperfusion, tFNA-TPP effectively enhanced mitophagic flux, as evidenced by a 4.2-fold increase in the LC3-II/LC3-I ratio and a reduction in p62 expression, facilitating the clearance of impaired mitochondria and the restoration of renal function. By concurrently addressing oxidative stress and mitochondrial integrity, our study establishes a versatile platform for organelle-level therapy, offering a transformative approach for treating AKI and other conditions driven by mitochondrial dysregulation.