Dual-Targeted Albumin Nanoparticles for the Co-Delivery of Low-Dose paclitaxel and PCSK9 Inhibitor in Melanoma Treatment.

The immunosuppressive microenvironment and impaired antigen presentation represent significant challenges in melanoma treatment. This study explores strategies to overcome these barriers by simultaneously inducing tumor cell immunogenic cell death (ICD) and enhancing antigen presentation. We developed hyaluronic acid/R8-RGD dual-modified albumin nanoparticles (HR/LDPP-NPs) designed to co-deliver low-dose paclitaxel (PTX) and the PCSK9 inhibitor PF-06446846. PTX induces ICD, releasing calreticulin (CRT), ATP, and HMGB1 danger signals, thereby transforming tumor cells into an in situ antigen source and initiating dendritic cell-mediated T-cell responses, akin to an intrinsic vaccine effect. Simultaneously, the inhibition of PCSK9 significantly upregulates tumor MHC-I expression, counteracting immune evasion. This synergistic approach, combining in situ vaccination with enhanced antigen presentation, significantly amplifies antitumor immunity. Both in vitro and in vivo experiments demonstrate that these spatiotemporally coordinated dual-targeting nanoparticles achieve substantial therapeutic efficacy with significantly reduced toxicity, presenting a novel chemo-immunotherapeutic strategy for melanoma treatment.