Targeted Delivery of The Pan-Inflammasome Inhibitor MM01 as An Alternative Approach to Acute Lung Injury Therapy.

Acute lung injury (ALI) is a severe pulmonary disorder responsible for high percentage of mortality and morbidity in intensive care unit patients. Current treatments are ineffective, so the development of efficient and specific therapies is an unmet medical need. The activation of NLRP3 inflammasome during ALI produces the release of proinflammatory factors and pyroptosis, a pro-inflammatory form of cell death that contributes to lung damage spreading. Here, we demonstrate that modulating inflammasome activation through inhibition of ASC oligomerization by the recently described MM01 compound could be an alternative pharmacotherapy against ALI. Besides, we determine the added efficacy of using a drug delivery nanosystem designed to target the inflamed lungs. The MM01 drug is incorporated into mesoporous silica nanoparticles capped with a peptide (TNFR-MM01-MSNs) to target TNFR-1 receptor to pro-inflammatory macrophages. The prepared nanoparticles can deliver the cargo in a controlled manner after the preferential uptake by pro-inflammatory macrophages and exhibit anti-inflammatory activity. Finally, the therapeutic effect of MM01 free or nanoparticulated to inhibit inflammatory response and lung injury is successfully demonstrated in LPS-mouse model of ALI. The results suggest the potential of pan-inflammasome inhibitors as candidates for ALI therapy and the use of nanoparticles for targeted lung delivery. This article is protected by copyright. All rights reserved.