Biomimetic anlotinib-loaded FePc-silicate nanoparticles for sonodynamic and immunotherapy in non-small cell lung cancer via dual PD-L1 modulation.

Non-small cell lung cancer (NSCLC) accounts for approximately 85 % of all lung cancer cases, in urgent need for multimodal therapeutic strategies. Sonodynamic therapy (SDT) has recently emerged as a promising non-invasive strategy. Programmed death-ligand 1 (PD-L1) antibody represented immunotherapy has shown limited efficacy due to inadequate tumor accumulation and persistent intracellular PD-L1 signaling. To address these challenges, we developed a multifunctional biomimetic nanodrug (APSNM), composed of iron phthalocyanine (FePc)-silicate nanoparticle (NP) and encapsulated Anlotinib, with PD-L1 coated macrophage membrane onto the surface. This design enables dual checkpoint inhibition by concurrently downregulating intracellular PD-L1 via p-VEGFR2/p-JAK2/p-STAT3 pathway suppression and blocking extracellular PD-L1 through antibody-mediated surface binding. Upon ultrasound activation, APSNM generates reactive oxygen species (ROS) and enhances antitumor immunity. Orthotopic lung tumor mouse model demonstrates that APSNM exhibits excellent tumor-targeting capability and enhanced antitumor efficacy compared to non-functionalized or non-ultrasound-treated controls. Notably, APSNM + US treatment led to the greatest tumor regression, increased CD4 and CD8 T cell infiltration, and elevated IFN-γ expression. These findings highlight APSNM as a promising nanoplatform for precise, multimodal NSCLC therapy via the integration of antiangiogenesis, sonodynamic therapy, and immune checkpoint modulation.