Efficient Co-Delivery of Metformin and Ammonia Borane via a Hollow Mesoporous Polydopamine Nanogenerator for Enhanced Chemo-Photothermal Therapy against Melanoma

Melanoma, a highly aggressive skin cancer, poses significant challenges due to its rapid metastases and high mortality rates. While metformin (Met), a first-line medication for type 2 diabetes, has shown promise in inhibiting tumor growth and metastases, its clinical efficacy in cancer therapy is limited by low bioavailability, short half-life, and gastrointestinal adverse reactions associated with oral administration. In this study, we developed a hollow mesoporous polydopamine nanocomposite (HMPDA-PEG@Met@AB) coloaded with Met and ammonia borane (AB), designed to enable a combined gas-assisted, photothermal, and chemotherapeutic approach for melanoma treatment. This system releases Met and H₂ in response to the acidic tumor microenvironment both in vitro and in vivo. The released H₂ facilitates nanocomposites escape from lysosomes and inhibits heat shock protein expression in B16-F10 cells. Concurrently, Met and H₂ disrupt the mitochondrial respiratory chain, reduce mitochondrial membrane potential, and inhibit ATP synthesis, ultimately activating AMPK signaling and suppressing mTOR activity. The system also elevates reactive oxygen species (ROS) levels, leading to tumor cell apoptosis. Under 808 nm near-infrared irradiation, the photothermal effect of HMPDA enhances Met release, further inhibiting tumor growth. In vivo experiments demonstrated efficient Met delivery, achieving therapeutic levels that activated AMPK in tumors without inducing hypoglycemia. These findings suggest that this drug delivery system holds significant clinical potential for melanoma treatment.