In Situ Engineered “Cascade‐Amplified” Drug‐Loaded Vesicles for Enhanced Cancer Stem Cell Therapy

Cancer stem cells (CSCs) characterized by the capacity of self-renewal and drug resistance, are a major cause of tumour recurrence and metastasis. However, CSCs are mainly localized in the deep and hypoxic regions of the tumour microenvironment that hinder drug penetration. Furthermore, their overexpression of the CD24/Siglec10 immune checkpoint axis markedly suppresses immune clearance, severely limiting the efficacy of current therapeutic strategies. To address this challenge, this study developed an in situ engineered "cascade-amplified" drug-loaded vesicle delivery system, aiming to achieve deep drug delivery into CSC-enriched regions and enhance anti-tumour immune responses. Based on a biomimetic "core-shell" nanoplatform (siXkr8/Dox@PMLC), this system initiates a cascade within the TME where Doxorubicin (Dox) induces tumour cells to generate drug-loaded apoptotic bodies (ApoBDs). These ApoBDs serve as primary vesicles that, upon uptake by adjacent tumour cells, trigger secondary apoptosis, establishing a "cascade-amplified" cycle of enhanced drug delivery. Meanwhile, the silencing of the phospholipid scramblase Xkr8 via siRNA inhibits phosphatidylserine (PS) exposure on the surface of ApoBDs, thereby preventing their recognition and clearance by M2-type macrophages and facilitating immune phenotype remodelling. Furthermore, through targeted blockade of the CD24/Siglec-10 immune axis, the nanoplatform enhances macrophage-mediated phagocytosis of CSCs. In summary, this strategy achieves deep eradication of CSCs and synergistically enhances anti-tumour immunotherapy, demonstrating significant translational potential.