Acoustic delivery of indocyanine green via biosynthetic gas vesicles for tumor photothermal therapy

Photothermal therapy (PTT) serves as a complementary strategy to conventional cancer treatments. Indocyanine green (ICG) is the only U.S. Food and Drug Administration (FDA)-approved photothermal agent. However, its clinical application is hindered by poor stability, short blood half-life, and lack of tumor targeting. Herein, we developed biosynthetic gas vesicles (GVs) covalently conjugated with ICG (ICG-GVs) for remotely controlled, visibly acoustic delivery of ICG to tumors in a subcutaneous xenograft model of MB49 murine bladder cancer in C57BL/6 mice. The resulting ICG-GVs exhibit uniform morphology (~200 nm) with an ICG loading rate of 58%, good colloidal stability, and enable trimodal imaging (ultrasound, near-infrared fluorescence, and photoacoustic) for real-time visualization of delivery. Pharmacokinetic analysis revealed that ICG-GVs significantly prolong ICG circulation half-life and increase AUC. Ultrasound-triggered GV cavitation enhanced intratumoral ICG delivery, achieving tumor temperatures >60 °C upon laser irradiation, leading to complete tumor regression and prolonged survival without detectable toxicity. This study provides a clinically translatable strategy for precise and effective ICG-based PTT.