Frontiers in immunology · 2026
Erythrocyte membrane-liposome coating sustains circulation stability and targeted tumor therapy of CAR-T cells.
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Chen Zhiying, Zhou Muya, Li Xiaoyu, Zhao Yuqi, Wang Zhengling, Hu Jinhua, Hong Jialu, Zhou Shenrui, Pan Feiyan, Hu Zhigang, He Lingfeng, Gao Tao, Jiang Xiaodong, Wang Zhiqiang, Guo Zhigang
Аннотация
BACKGROUND: CAR-T therapy is limited by off-target sequestration in liver, spleen, and lungs, which reduces tumor delivery and risks systemic toxicity. Genetic engineering approaches are complex and carry safety concerns, necessitating efficient non-genetic strategies to optimize CAR-T biodistribution.
PURPOSE: We developed red blood cell membrane-chimeric liposomes (Rlip) as a biomimetic coating system to non-genetically modify CAR-T cells, aiming to enhance immune evasion, prolong circulatory persistence, and redirect trafficking toward tumors while preserving intrinsic effector function.
METHODS: Rlip-CAR-T cells were prepared via simple incubation. In vitro characterization assessed coating stability, CD47-mediated macrophage resistance, phenotype preservation, and antigen-specific cytotoxicity. In vivo studies evaluated biodistribution, tumor infiltration, and efficacy in Nalm-6 systemic leukemia and 1806-luc subcutaneous ovarian cancer models.
RESULTS: Rlip coating stably presented CD47, functionally impairing macrophage phagocytosis and enhancing peripheral persistence without altering memory subsets, activation markers, or cytotoxicity. Rlip-CAR-T cells demonstrated markedly reduced off-target organ accumulation and increased intratumoral enrichment in both models, with superior tumor control and prolonged survival observed in the leukemia model.
CONCLUSIONS: Rlip surface engineering represents a universal, clinically translatable strategy to overcome CAR-T biodistribution barriers. By integrating erythrocyte-mimetic immune evasion with optimized tumor delivery, this approach improves CAR-T cell accumulation at tumor sites across hematologic and solid malignancies.
PURPOSE: We developed red blood cell membrane-chimeric liposomes (Rlip) as a biomimetic coating system to non-genetically modify CAR-T cells, aiming to enhance immune evasion, prolong circulatory persistence, and redirect trafficking toward tumors while preserving intrinsic effector function.
METHODS: Rlip-CAR-T cells were prepared via simple incubation. In vitro characterization assessed coating stability, CD47-mediated macrophage resistance, phenotype preservation, and antigen-specific cytotoxicity. In vivo studies evaluated biodistribution, tumor infiltration, and efficacy in Nalm-6 systemic leukemia and 1806-luc subcutaneous ovarian cancer models.
RESULTS: Rlip coating stably presented CD47, functionally impairing macrophage phagocytosis and enhancing peripheral persistence without altering memory subsets, activation markers, or cytotoxicity. Rlip-CAR-T cells demonstrated markedly reduced off-target organ accumulation and increased intratumoral enrichment in both models, with superior tumor control and prolonged survival observed in the leukemia model.
CONCLUSIONS: Rlip surface engineering represents a universal, clinically translatable strategy to overcome CAR-T biodistribution barriers. By integrating erythrocyte-mimetic immune evasion with optimized tumor delivery, this approach improves CAR-T cell accumulation at tumor sites across hematologic and solid malignancies.