Ultrasound-activated dual-defensive nanoprotectant breaks the NAD + vicious cycle to suppress NLRP3-mediated pyroptosis in myocardial ischemia/reperfusion injury

Rationale: Cardiovascular disease imposes a substantial health burden worldwide and remains the primary cause of global mortality, with acute myocardial infarction (AMI) being the most severe acute manifestation.Despite the clinical benefits of reperfusion therapy, the accompanying ischemia/reperfusion (I/R) injury often triggers irreversible myocardial damage through NLRP3 inflammasome-mediated pyroptosis and oxidative stress, for which no effective targeted therapy currently exists.Hence, novel effective therapies for AMI-related I/R injury are urgently required clinically.Methods: We developed a novel nanoprotectant ( IMTP Lip@HNP) via the double-emulsification method, which exerts dual functions: NAD⁺ replenishment and ROS scavenging.Using hollow mesoporous Prussian blue (HMPB) nanozymes as core, we loaded nicotinamide mononucleotide (NMN), emulsified with perfluoropentane for ultrasound-controlled release, and encapsulated in IMTP-functionalized lipid bilayers for targeting.We validated efficacy by assessing ROS clearance, NAD⁺ restoration, NLRP3 deacetylation, and pyroptosis suppression, alongside 3D imaging and transcriptomic analysis.Results: IMTP Lip@HNP targeted and accumulated in ischemic myocardium.It exhibited potent catalase-and superoxide dismutase-like activities, eliminating ROS and restoring intracellular NAD⁺ levels.Elevated NAD⁺ further facilitated SIRT2mediated NLRP3 deacetylation and thereafter blocked downstream pyroptotic signaling cascades.In vivo animal assays verified decreased myocardial fibrosis, improved angiogenesis and reversal of pathological cardiac remodeling.Transcriptome sequencing data identified upregulated genes related to mitochondrial oxidative phosphorylation, which confirmed multi-level cardioprotective effects of the formulation.Conclusions: The IMTP Lip@HNP nanoplatform synergistically strengthens endogenous antioxidant defense, restrains pyroptosis progression and optimizes mitochondrial homeostasis, thus effectively alleviating post-AMI myocardial I/R injury.This combinatorial nanotherapeutic strategy possesses promising translational prospect for mitigating I/R lesion and improving longterm prognosis of AMI patients.