Carrier-free delivery of thymopentin-regulated injectable nanogels via an enhanced cancer immunity cycle against melanoma metastasis.

Thymopentin (TP5), a clinically used immunomodulatory pentapeptide, can efficiently promote thymocyte differentiation and influence mature T-cell function, thus playing an essential role in the cancer immunotherapy. However, the excellent water solubility and high IC50 of TP5 result in an uncontrolled release behavior, requiring a high loading efficiency to achieve high dosage. Here in, we reported that TP5, combined with specific chemotherapeutic agents, can co-assemble into nanogels due to multiple hydrogen bonding sites. The co-assembly of TP5 with chemotherapeutic agent doxorubicin (DOX) into a carrier-free and injectable chemo-immunotherapy nanogel can enhance the cancer immunity cycle against melanoma metastasis. In this study, the designed nanogel guarantees high drug loading of TP5 and DOX and ensures a site-specific and controlled release of TP5 and DOX with minimal side effects, thus addressing the bottlenecks encountered by current chemo-immunotherapy. Moreover, the released DOX can effectively induce tumor cell apoptosis and immunogenic cell death (ICD) to activate immune initiation. Meanwhile, TP5 can significantly promote the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to amplify the cancer immunity cycle. As a result, this nanogel shows excellent immunotherapeutic efficacy against melanoma metastasis, as well as an effective strategy for TP5 and DOX application.