AbstractBackground and PurposeMyocardial dysfunction is a significant complication associated with sepsis. However, there are currently no specific and effective treatments available. Inhibiting gasdermin D (GSDMD)‐mediated pyroptosis has shown promise in mitigating sepsis‐induced myocardial dysfunction. The GSDMD inhibitor Y2 (GI‐Y2) has been demonstrated to directly bind to GSDMD. Nonetheless, it remains uncertain whether GI‐Y2 offers a cardioprotective effect in the context of sepsis‐induced myocardial dysfunction.Experimental ApproachA mouse model of sepsis was created using lipopolysaccharide (LPS), caecal ligation and puncture. Following treatment with GI‐Y2 or macrophage membrane‐encapsulated GI‐Y2 nanoparticles (GI‐Y2@MM‐NPs), myocardial dysfunction and pyroptosis levels in heart tissues were assessed. Transcriptome sequencing revealed the molecular mechanism of GI‐Y2 in treating septic cardiomyopathy.Key ResultsWe observed that GI‐Y2 alleviated myocardial dysfunction and attenuated cardiac inflammation in mice induced by LPS, caecal ligation and puncture. GI‐Y2 reduced macrophage pyroptosis and attenuated macrophage‐mediated cardiomyocyte injury induced by LPS/nigericin. Concurrently, we confirmed the protective effect of GI‐Y2 against LPS‐induced cardiac dysfunction was abolished in the absence of GSDMD. Additionally, GI‐Y2 attenuated the mitochondrial damage induced by LPS by inhibiting GSDMD in the mitochondria. Furthermore, we developed GI‐Y2@MM‐NPs to enhance the targeting capability of GI‐Y2 towards macrophages in heart tissues and demonstrated its protective effect in vivo.Conclusion and ImplicationsThese findings indicate that GI‐Y2 alleviates septic myocardial injury and dysfunction by specifically targeting GSDMD, thereby inhibiting GSDMD‐mediated pyroptosis and mitochondrial damage. Both GI‐Y2 and GI‐Y2@MM‐NPs may serve as promising therapeutic options for addressing septic myocardial dysfunction.