Dendritic Cell-Derived Exosomes Driven Drug Co-Delivery Biomimetic Nanosystem for Effective Combination of Malignant Melanoma Immunotherapy and Gene Therapy

Abstract

Purpose Malignant melanoma (MM), the most lethal skin cancer, is highly invasive and metastatic. These qualities are related to not only genetic mutations in MM itself but also the interaction of MM cells with the immune system and microenvironment. This study aimed to construct a combined immunotherapy and gene therapy drug delivery system for the effective treatment of MM. Methods Mature dendritic cell (mDC) exosomes (mDexos) with immune induction functions were used as carriers. BRAF siRNA (siBRAF) with the ability to silence mutated BRAF in MM was encapsulated in mDexos by electroporation to construct a biomimetic nanosystem for the codelivery of immunotherapy and gene therapy drugs (siBRAF-mDexos) to the MM microenvironment. Then, we investigated the nanosystem’s serum stability and biocompatibility, uptake efficiency in mouse melanoma cells (B16-F10 cells), cytotoxicity against B16-F10 cells and inhibitory effect on BRAF expression. Furthermore, we evaluated its antimelanoma activity and safety in vivo. Results SiBRAF-mDexos were nanosized. Compared to siBRAF, siBRAF-mDexos displayed significantly increased serum stability, biocompatibility, uptake efficiency in B16-F10 cells, and cytotoxicity to B16-F10 melanoma cells; they also had a significantly greater inhibitory effect on BRAF expression and induced T-lymphocyte proliferation. Moreover, compared with siBRAF, siBRAF-mDexos showed significantly enhanced anti-MM activity and a high level of safety in vivo. Conclusion The study suggests that the siBRAF-mDexo biomimetic drug codelivery system can be used to effectively treat MM, which provides a new strategy for combined gene therapy and immunotherapy for MM.

Engineered biological nanoparticles as nanotherapeutics for tumor immunomodulation

“…These nanoscale vesicles, sourced from T-cells, macrophages, dendritic cells (DCs), and natural killer (NK) cells, are adept at antigen presentation and can be tailored to deliver specific therapeutic payloads. 211–214 Their role in priming the immune system and synergistic effects with existing therapies, such as immune checkpoint inhibitors, are highlighted.…”

“…240 The mDexos exhibited significantly greater inhibitory effect on BRAF expression, induced T-lymphocyte proliferation, and inhibited the growth of subcutaneous metastatic melanoma in mice. 212 Similarly, macrophage-derived exosomes have been engineered to deliver ferroptosis factors, RSL-3 to target tumor cells (Fig. 17B).…”