Advanced science (Weinheim, Baden-Wurttemberg, Germany)Sep 2, 2026

Nanoparticles Targeting Mitochondria Reduce Inflammation Caused by Damaged Mitochondrial DNA

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Sep 3, 2026

Abstract

A small molecule inhibitor designed to target mitochondrial flap endonuclease 1 reduces leakage of oxidized mitochondrial DNA fragments.

Oxidized mitochondrial DNA fragments trigger inflammation that can harm cells and tissues.
A novel delivery system using hyaluronic acid and selenium nanoparticles encapsulates the inhibitor to enhance targeting and efficiency.
The inhibitor prevents the cleavage of oxidized mitochondrial DNA, which may reduce its leakage from damaged mitochondria.
In a model of acute respiratory distress syndrome, the delivery system suppresses inflammatory signaling related to oxidized mitochondrial DNA.
The approach may provide a therapeutic strategy for conditions driven by oxidized mitochondrial DNA inflammation.

Simplified

Oxidized mitochondrial DNA (Ox-mtDNA) fragments escaping from mitochondria trigger a potent inflammatory cascade that endangers cellular and tissue integrity. Strategies against pre-existing mtDNA-driven inflammation have been developed. However, the inhibition of emerging Ox-mtDNA fragments remains a critical challenge due to continual leakage from stressed mitochondria. Here, we present a source-control nanodelivery strategy that targets Ox-mtDNA to prevent the generation of fragments and eliminate existing ones. To this end, a small molecule inhibitor FI is specifically designed to selectively target mitochondrial flap endonuclease 1 (mitochondrial FEN1), thereby inhibiting Ox-mtDNA cleavage and the subsequent leakage of fragments. To facilitate the precise and efficient delivery of FI to inflammation-associated cells, we engineered a hyaluronic acid (HA) functionalized nanocarrier, designated Se-FI@Lip-HA, which encapsulates selenium nanoparticles bearing FI (Se-FI NPs) within phospholipid vesicles. The SeNPs further scavenge reactive oxygen species (ROS) and promote autophagy-mediated clearance of leaked mtDNA. Acute respiratory distress syndrome (ARDS), as a severe inflammatory lung disorder, is used as a proof-of-concept model. Se-FI@Lip-HA multimodally suppresses inflammatory signaling activated by Ox-mtDNA at the source and effectively alleviates lung tissue injury. This strategy offers a broadly applicable therapeutic avenue for Ox-mtDNA-driven pathologies in ARDS and other inflammatory diseases.

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Nanoparticles Targeting Mitochondria Reduce Inflammation Caused by Damaged Mitochondrial DNA

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