A phosphatidylserine-targeted self-amplifying nanosystem improves tumor accumulation and enables efficient tumor...

Tumor heterogeneity disrupts the consistent expression of target markers, leading to inefficient tumor targeting and contributing to drug resistance and relapse. Therefore, seeking a more universal target is crucial for enhancing drug enrichment in tumors. In this study, we propose a self-amplifying tumor-targeting strategy that leverages externalized phosphatidylserine (PtdSer) on apoptotic cells as a universal target. The system is composed of a Red Blood Cell-Liposome hybrid membrane camouflaged Mn-Ce6 nanocomplex, which is further modified with a PtdSer aptamer (MC@RL/Apt). MC@RL/Apt demonstrates prolonged circulation time and enhanced tumor accumulation, capable of inducing cancer cell apoptosis and PtdSer externalization under 660 nm light irradiation. The externalized PtdSer is then recognized by the PtdSer aptamer, which recruits additional MC@RL/Apt to the tumor site, facilitating a self-amplified tumor accumulation effect. In vitro studies show that MC@RL/Apt acted as an efferocytosis inhibitor, suppressing macrophage phagocytosis of apoptotic cells and promoting macrophage polarization toward the pro-inflammatory M1 phenotype. Compared to non-functionalized MC@RL, intravenous administration of MC@RL/Apt increases tumor accumulation by 1.46-fold under 660 nm light irradiation. As a result, treatment with MC@RL/Apt effectively suppressed tumor growth and induced robust antitumor immune responses. This work highlights a self-amplifying tumor-targeting strategy that leverages externalized PtdSer on apoptotic cells as a target to enhance tumor-specific drug delivery, while simultaneously inhibiting PtdSer-mediated macrophage engulfment, offering a promising approach for improving cancer therapy outcomes.