Abstract

Mitocytosis is a compensatory pathway responding to mitochondria stress in migratory cells, which expels damaged mitochondria through migrasomes, preserving mitochondrial homeostasis and cellular viability. We found distinct responses to mitochondria-targeted therapy across breast tumor models distinguished by migrasome expression (4T1 > E0771 > EMT6). The antimetastatic efficacy of mitochondrial damage was notably compromised in the migrasome-high 4T1 tumor model due to robust mitocytosis activation, which is merely explored and lacks effective strategy. Here, we developed a mitochondria-targeted nanoplatform (RH-NPs) with the functions of mitocytosis inhibition and mitochondrial damage. Mitochondria-targeted triphenylphosphonium-modified lonidamine (TPP-LND) and integrin inhibitor cilengitide (CGT) were separately loaded into a nanodelivery system (TL/RH-NPs and CGT/RH-NPs, respectively). TL/RH-NPs effectively targeted and damaged tumor mitochondria. Simultaneously, upon mitocytosis activation, CGT/RH-NPs hitchhiked with damaged mitochondria into migrasomes to block mitocytosis via integrin inhibition. This strategy significantly potentiated antimetastatic efficacy in 4T1 tumor models, which established an effective approach for mitocytosis modulation and optimization of mitochondria-targeted therapies.