Biomimetic liposomal nanovesicles remodel the tumor immune microenvironment to augment sono-immunotherapy.

Sonodynamic therapy (SDT)-mediated immunogenic cell death and immune checkpoint blockade offer new opportunities for tumor treatment. However, challenges including immunosuppression, hypoxic tumor microenvironments, and inadequate drug delivery hinder therapeutic efficacy. Therefore, we developed a multifunctional biomimetic liposome microbubble named H-R@Lip@M, which is coated with melanoma cell membranes, contains perfluoropentane as its core, and is loaded with the sonosensitizer hematoporphyrin monomethyl ether and the immune adjuvant resiquimod. The targeting properties of melanoma cell membranes enable effective accumulation of nanoparticles (NPs) at tumor sites. Equipped with ultrasonic/photoacoustic imaging capabilities, these NPs allow precise control over the release of drugs and oxygen upon ultrasound stimulation. In vitro and in vivo results consistently showed that the NPs enhanced anti-tumor efficacy, halting primary tumor progression and preventing lung metastasis. Moreover, SDT increased reactive oxygen species levels within tumors, preferentially inducing apoptosis while maximizing immunogenic cell death. When combined with PD-L1 blockade, this synergy promotes dendritic cell maturation and alters various immune populations, boosting T-cell infiltration while enhancing M1 macrophage polarization and reducing regulatory T-cell presence. In summary, the proposed combination has the potential to synergistically enhance the efficacy of sono-immunotherapy by remodeling the immunosuppressive microenvironment, providing valuable insights for addressing challenges associated with SDT-based cancer therapy.