Targeting the NLRP3 inflammasome with natural products for ischemia-reperfusion injury across organs: mechanisms, structure-activity relationships, and delivery innovations.

The review provides a comprehensive study of the therapeutic potential of natural products targeting the NLRP3 inflammasome to mitigate ischemia/reperfusion (I/R) injury across multiple organs. Excessive activation of the NLRP3 inflammasome triggers inflammatory cascades, cytokine release, pyroptosis, and tissue damage that exacerbate I/R injury in conditions such as ischemic stroke, myocardial infarction, and organ transplantation. It emphasizes the central pathological role of NLRP3 inflammasome activation in I/R injury and the critical need for effective inhibitors. It systematically presents pharmacological mechanisms of various phytochemicals-including glycyrrhizin, isoliquiritigenin, celastrol, colchicine, curcumin, quercetin, ferulic acid, and resveratrol-and their specific inhibitory actions on NLRP3 via ASC oligomerization, caspase-1 activation, NF-κB signaling, ROS production, and potassium efflux pathways. The manuscript also discusses challenges related to poor bioavailability and rapid metabolism of these natural compounds. It outlines innovative formulation strategies, including lipid nanoparticles, liposomes, polymeric carriers, and mesoporous silica nanoparticles, which enhance pharmacokinetics, stability, targeted delivery, and blood-brain barrier penetration, thereby amplifying therapeutic efficacy. In vitro and in vivo studies consistently show that these phytoconstituents reduce infarct size, inflammatory cytokine levels, oxidative stress, and pyroptosis, promoting cell survival and functional recovery after I/R injury. The review underscores the translational promise of combining traditional medicinal knowledge with advanced nanotechnology to develop safer and more effective multi-targeted therapies for I/R-related diseases. Overall, this manuscript highlights natural NLRP3 inflammasome inhibitors as a promising therapeutic paradigm that merits further clinical development to address the unmet needs in I/R injury management.