A Green Self-Assembled Nanoplatform of 10-Hydroxycamptothecin and Cordyceps Polysaccharides for Dual Anti-Tumor Efficacy Through Apoptosis and Immune Modulation

<b>Background:</b> Melanoma is one of the most dangerous types of skin cancer, with its global incidence having surged in recent years. There exists an urgent clinical need for novel therapeutic strategies that combine high efficacy, low toxicity, and multiple mechanisms of action. <b>Methods:</b> This study applies a "Property Optimization and Therapeutic Synergy" strategy, selecting the natural active polysaccharide component, <i>Cordyceps</i> polysaccharides (WCP), as a functional carrier to encapsulate the broad-spectrum chemotherapeutic agent, 10-Hydroxycamptothecin (10HCPT, HCPT). Leveraging non-covalent interactions between the two components, a self-assembly nanoscale drug delivery system (H-W NPs) with high stability and dual antitumor activity was constructed to achieve more efficient and precise antitumor effects. <b>Results:</b> The H-W NPs demonstrated outstanding antitumor efficacy both in vitro and in vivo. The H-W NPs achieved a threefold increase in the inhibition rate against B16-F10 cells compared to free HCPT in vitro and demonstrated a remarkable tumor inhibition rate of 95.08% in vivo. The therapeutic effect may be attributed to the dual antitumor mechanisms of the H-W NPs. Mechanistic studies revealed a synergistic dual-mode of action driving this potent efficacy. Firstly, H-W NPs efficiently induced caspase-3-mediated apoptosis in tumor cells. RNA sequencing analysis suggested the involvement of pathways related to cell cycle arrest and apoptosis. Additionally, H-W NPs promoted the expansion and activation of CD8⁺ T cells in the spleen. These activated cytotoxic T cells reinforced the apoptotic cascade, effectively amplifying the caspase-3-mediated death signal. <b>Conclusions:</b> In summary, the self-assembly nanoscale drug system achieved potent antitumor efficacy through the synergistic action of direct tumor cell killing and immune modulation, offering a highly promising strategy for the development of novel formulations against melanoma.