Ultrasound-targeted delivery of total extracts from Abelmoschus Manihot (L.) alleviates radiation-induced cardiomyocyte ferroptosis via the NOX4/SLC7A11/GPX4 axis

Radiotherapy is a standard treatment for thoracic malignancies, but it frequently leads to radiation‑induced heart disease (RIHD), a serious and dose‑limiting complication for which no targeted therapies are currently available. Total extracts from Abelmoschus manihot (L.) (TEA), known for their cardioprotective properties, are widely used in treating various ischemic heart diseases. Here, we identify ferroptosis driven by the NOX4/SLC7A11/GPX4 axis as a core mechanism of RIHD, with GPX4 serving as the non‑redundant downstream executor. TEA effectively modulates this axis; however, it lacks cardiac selectivity, which may compromise antitumor efficacy. To overcome this barrier, we developed, characterized, and evaluated a novel nanoplatform consisting of TEA‑loaded PLGA nanoparticles conjugated with a primary cardiomyocyte‑specific homing peptide (PCM), further integrated with low-intensity focused ultrasound (LIFU)‑triggered on‑demand release (TEA@PLGA‑PCM). This system achieves superior myocardial accumulation, effectively improves cardiac function, reverses pathological remodeling, and normalizes ferroptosis markers as well as NOX4/SLC7A11/GPX4 protein expression. In summary, we successfully constructed a novel nanoplatform that represents a promising strategy for integrated targeted delivery and synergistic therapy in RIHD management.