CD-73 blocking black phosphorus nanosheets hitchhiked on erythrocytes via affinity difference of AS1411 aptamer for targeted photothermal-immunotherapy of lung cancer.

Metabolic checkpoint inhibition targeting adenosine signaling combined with photothermal therapy (PTT) can remodel the immunosuppressive tumor microenvironment and enhance antitumor immunity in lung cancer, but its efficacy is limited by tumor-targeted accumulation. Leveraging the differential binding affinity of AS1411 aptamer (Apt) for nucleolin and actin, we developed an erythrocytes-based nanodelivery system incorporating red blood cell (RBC), black phosphorus nanosheets (BPs), the CD73 inhibitor AMPCP, and Apt. The Apt binds to actin on RBC membranes, facilitating BPs and AMPCP loading and enabling RBC hitchhiking to prolong systemic circulation and enhance tumor accumulation. At the tumor site, the higher affinity for nucleolin of aptamer triggers the release of BPs and AMPCP, which combinedly increase dendritic cell maturation and expand CD8+ T cells, while reducing regulatory T cells and myeloid-derived suppressor cells. The combined PTT and CD-73 blockade reshapes the immunosuppressive microenvironment and boosts potential antitumor immunity, significantly suppresses lung cancer growth. This RBC-based delivery strategy facilitates targeted nanomedicine accumulation and robust antitumor immune activation, providing an effective platform for lung cancer suppression.