ABSTRACT
Malignant melanoma, as a highly aggressive skin cancer, is strongly associated with mutations in serine/threonine protein kinase B-RAF (BRAF, where RAF stands for rapidly accelerated fibrosarcoma). Targeted therapy with anti-BRAF small interfering RNA (siBRAF) represents a crucial aspect of metastatic melanoma treatment. In this study, an injectable hydrogel platform based on sodium alginate (SA), with multifunctions of photothermal and Ca2+-overload cell apoptosis, was explored as a siBRAF carrier for metastatic melanoma therapy. We employed polydopamine nanoparticles (PDAs) as a photothermal core and constructed a calcium phosphate (CaP) shell via biomineralization (PDA@CaP) to load siBRAF (PDA@siBRAF/CaP). The pH-sensitive CaP shell facilitated the release of Ca2+ under the weakly acidic tumor microenvironment, triggering the gelation of PDA@siBRAF/CaP-SA to localized release siBRAF at tumor sites with the interruption of the RAS-RAF-MEK-ERK (MAPK) pathway. Besides, the continuous release of Ca2+ could also lead to Ca2+-overload cell apoptosis. Moreover, the photothermal effect of PDA regulated the release kinetics, resulting in coordinated therapeutic abilities of individual components in the PDA@siBRAF/CaP-SA hydrogels. Consequently, the effective inhibition of tumor growth and metastasis was achieved in vitro and in vivo using a highly metastatic melanoma cell line B16F10 as the model, by combining photothermal ablation, Ca2+ overload, and BRAF silencing. Our work provides a proof-of-concept for an injectable hydrogel system that simultaneously targets multiple mechanisms involved in melanoma progression and has the potential to be translated into clinical use for the metastatic melanoma therapy.