Ion-Gradient Driven Drug-Loading Liposomes for Codelivery of Shikonin/Regorafenib for Cancer Immunometabolic Therapy and Postoperative Intervention.

Lactate emerges as a pivotal immunometabolite in tumor progression, orchestrating immunosuppression by polarizing tumor-associated macrophages (TAMs) toward pro-tumor M2 phenotypes and activating immunosuppressive cell populations. Targeting intratumoral lactate has emerged as a promising therapeutic strategy for tumors with poor immune responses. Shikonin (SHK) inhibited the lactate production of tumor cells by targeting pyruvate kinase M2 (PKM2). Regorafenib (REGO), an FDA-approved multikinase inhibitor, repolarized TAMs from M2-like to tumor-suppressive M1 phenotypes. To overcome their clinical limitations of off-targeting and systemic toxicity, a T12 peptide-modified liposome (T12-SR-LP) was constructed to encapsulate SHK and REGO through an ion-gradient method. T12-SR-LP exhibited a high total drug loading efficiency of 10.5%, attributed to copper ion-mediated coordination. Furthermore, the hydrogel with T12-SR-LP (T12-SR-LP@Gel) significantly suppressed tumor growth and recurrence compared to controls. This study highlighted T12-SR-LP as a promising strategy targeting both the metabolic and immune facets of the tumor microenvironment to combat "cold" tumors with poor immune activity.