Magnetically navigated nano-PROTAC ameliorates acute lung injury.

Introduction: Acute lung injury (ALI) is an acute inflammatory lung disease with high rates of morbidity and mortality. The lack of efficient pharmacological treatments for ALI resulted in poor outcomes and prognosis.

Methods: Poly(lactic-co-glycolic acid) (PLGA) was used to carry magnetic nanoparticles and TRIM24-targeted PROTAC (dTRIM24), which was further camouflaged with the exosome membranes derived from M1 macrophages to obtain nano-PROTAC (EM/PLGA/Magnetic nanoparticles/dTRIM24, EMPLANT). We evaluated the nanoparticles on the physicochemical properties, cellular uptake, in vitro toxicity, anti-inflammatory effects, in vivo biodistribution, in vivo therapeutic effect, anti-inflammatory capacity, and in vivo safety.

Results: This nano-PROTAC EMPLANT, shows dual-targeting capability by magnetic navigation and inflammatory specificity. EMPLANT selectively accumulates in the inflammatory lungs in ALI model mice under an external magnetic field, reduces lung injuries, and drastically prolongs survival. Mechanistically, the degradation of TRIM24 upregulates the expression of STAT6 and thus promotes an efficient phenotypic switch of macrophages from M1 to M2. This strategy can ameliorate ALI greatly and increase the survival ratio to nearly 100%.

Conclusion: The nano-PROTAC demonstrates a promising therapeutic strategy for ALI through precisely in situ reprogramming macrophages. To the best of our knowledge, we are the first to develop this type of magnetically navigated artificial exosomes to deliver PROTAC and use it for ALI treatment.