Erythrocyte membrane-liposome coating sustains circulation stability and targeted tumor therapy of CAR-T cells

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.

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.

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.

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.

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.