Mitochondria-Inspired Nanoparticles with Microenvironment-Adapting Capacities for On-Demand Drug Delivery after Ischemic Injury

Stimuli-responsive nanoparticles (NPs), so-called "smart" NPs, possess great potentials in drug delivery. Presently, the intelligence of smart NPs is mainly based on their chemical or physical changes to stimuli, which are usually "mechanical" and fundamentally different from biological intelligence. Inspired by mitochondria (MT), a biosmart nanoparticle with microenvironment targeting and self-adaptive capacity (MTSNP) was fabricated for ischemic tissue repair. The nanoparticles were designed as shell@circular DNA@shell@core. The double shells were like the two-layered membranes of MT, the melatonin-loaded cores corresponded to the MT matrix, and the circular DNA corresponded to MTDNA. In function, melatonin-loaded cores simulated the cell-protective mechanism of MT, which naturally synthesized melatonin to resist ischemia, while circular DNA was constructed to mimic the biological oxygen-sensing mechanism, synthesizing VEGF for vascularization according to oxygen level, like the ATP supply by MT according to microenvironment demand. At the acute stage of ischemia, melatonin was rapidly released from MTSNP to scavenge reactive oxygen species and activated melatonin receptor I on MT to prevent cytochrome c release, which would activate apoptosis. During the chronic stage, circular DNA could sense hypoxia and actively secrete VEGF for revascularization as a response. Importantly, circular DNA could also receive feedback of revascularization and shut down VEGF secretion as an adverse response. Then, the therapeutic potentials of the MTSNP were verified in myocardial ischemia by the multimodality of the methods. Such nanoparticles may represent a promising intelligent nanodrug system.