Ultrasound-triggered dual-mode therapy for heart failure via synchronized electrical stimulation and nitric oxide release.

The multifaceted pathophysiology of heart failure demands therapeutic strategies that can concurrently address its electrophysiological and metabolic components. Here, we report a lead-free and battery-free piezoelectric nanoplatform that, under ultrasound irradiation, serves as a dual-mode platform to simultaneously generate localized electrical stimulation and trigger spatiotemporally controlled nitric oxide (NO) release. In a mouse model of pressure-overload-induced heart failure, this ultrasound-driven regimen restored cardiac contractile function, reversed pathological remodeling, and suppressed arrhythmogenesis. Integrated transcriptomic and proteomic analyses revealed that the therapeutic benefits were mediated by the combined action of electrical stimulation and nitric oxide. Electrical stimulation restored autonomic nervous system balance, and the two factors jointly reprogrammed sphingolipid metabolism to ameliorate mitochondrial dysfunction and oxidative stress. This work offers a paradigm for wire-free, multi-mechanistic cardiac therapy that leverages the non-invasiveness of ultrasound to concurrently rectify electrical and metabolic dysfunctions in the failing heart.