双靶向铁蛋白纳米笼增强贝του利酸治疗转移性黑色素瘤的疗效

Abstract

Dual-targeting cHFn@BA enables efficient delivery of betulinic acid to melanoma. • cHFn@BA synergistically targets TfR1 and αvβ3 integrin for enhanced uptake. • Ferritin nanocages exhibit high drug loading and pH-responsive release behavior. • cHFn@BA suppresses melanoma growth and metastasis with favorable biosafety. • cHFn@BA induces ROS-mediated mitochondrial apoptosis via PI3K/AKT regulation. Malignant melanoma is among the most aggressive and treatment-refractory skin malignancies, characterized by rapid metastatic progression, pronounced molecular heterogeneity, and frequent therapeutic resistance, all of which severely limit current treatment efficacy. Betulinic acid (BA), a naturally derived pentacyclic triterpenoid, has emerged as a promising anti-melanoma agent owing to its intrinsic tumor-selective cytotoxicity and potent induction of mitochondrial apoptosis. However, its clinical translation is markedly constrained by poor aqueous solubility, limited tumor selectivity in vivo, and rapid systemic clearance. Here, we report a dual-targeting ferritin nanocage nanotherapeutic for precision melanoma therapy by engineering a cyclic RGD peptide-functionalized human heavy-chain ferritin platform for efficient BA delivery (cHFn@BA). The biomimetic nanocage maintains structural integrity while achieving high drug loading, with up to 308 BA molecules encapsulated per nanocage, substantially improving drug dispersibility and delivery efficiency. By synergistically integrating intrinsic transferrin receptor 1 (TfR1)-mediated tumor tropism of HFn with αvβ3 integrin targeting conferred by cRGD, cHFn@BA enables enhanced tumor-selective uptake and intracellular delivery. Consequently, cHFn@BA exhibits substantially improved in vitro antitumor potency, with 4.5-fold and 1.7-fold reductions in IC₅₀ relative to free BA and non-modified HFn@BA, respectively, alongside enhanced apoptosis induction. In subcutaneous melanoma and pulmonary metastasis models, cHFn@BA robu