Abstract

Rationale Sonodynamic therapy (SDT) has emerged as a promising strategy for melanoma treatment because of its noninvasive nature, deep penetration and potential to activate antitumor immunity. However, the uncontrollable delivery and limited tumor accumulation of sonosensitizers often restrict SDT efficacy. And tumor cells tend to activate cytoprotective autophagy under SDT-induced oxidative stress, which may further compromise treatment outcomes. Developing an image-guided drug delivery system with the function of enhancing SDT efficacy offers a promising strategy for melanoma management. Methods We developed a new ultrasound (US)-responsive lipoic acid-based nanodroplets loaded with perfluoropentane (PFP) and sonosensitizer Chlorin e6 (LA@P-Ce6 NDs). The physicochemical properties, acoustic droplet vaporization (ADV) behavior, and biosafety of LA@P-Ce6 NDs were systematically evaluated. Contrast-enhanced ultrasound (CEUS) and photoacoustic (PA) imaging were conducted both in vitro and in vivo to evaluate multimodal imaging ability. Antitumor effects and mechanisms of LA@P-Ce6 NDs under US irradiation were investigated both in vitro and in vivo , as well as their ability to activate antitumor immunity. Results LA@P-Ce6 NDs exhibited excellent stability under physiological conditions and underwent effective ADV, enabling CEUS and PA imaging both in vitro and in vivo . Under therapeutic US, Ce6 induced strong ROS production and LA modulated autophagic flux, synergistically achieving enhanced oxidative damage at the irradiated site and promoting ICD. Our treatment showed significant antitumor ability and induced strong antitumor immune effect, which was able to suppress pulmonary metastasis. Conclusions This study presented a multifunctional LA@P-Ce6 NDs system that enabled autophagy-modulated, CEUS/PA image-guided SDT. The integration of multimodal imaging and synergistic antitumor therapy offers a promising melanoma management method.