Targeting mRNA delivery using bio-inspired hybrid cell membrane-incorporated liposomes: a novel strategy for cancer therapy.

Messenger RNA (mRNA) therapeutics have attracted considerable interest in cancer immunotherapy owing to their capacity for safe, transient, and controllable protein expression without the risk of genomic integration. However, clinical translation remains limited by the shortcomings of conventional lipid nanoparticles (LNPs), including poor mRNA stability, inefficient cellular uptake, limited endosomal escape, unintended immune activation, and inadequate tumor targeting. Bio-inspired hybrid cell membrane-incorporated liposomes address these limitations by integrating the structural stability and tunability of synthetic liposomes with natural cell membranes derived from erythrocytes, platelets, immune cells, or cancer cells. These hybrid systems leverage native proteins, such as cluster of differentiation 47 (CD47) for immune evasion, integrins and adhesion molecules for prolonged circulation, chemokine receptors for tissue homing, and tumor antigens for active targeting through homotypic binding and receptor-mediated interactions. Following cellular internalization, fusogenic lipids and fusion proteins promote endosomal disruption, facilitating efficient cytosolic release of mRNA and resulting in superior transfection compared with conventional LNPs. Beyond delivery, these platforms can modulate immune responses by functioning either as immunologically inert carriers that minimize off-target effects or as immunostimulatory vectors that enhance antigen presentation, dendritic cell activation, macrophage repolarization, and CD8⁺ T-cell priming. Preclinical studies demonstrate robust antitumor efficacy with an acceptable safety profile, as evidenced by normal serum alanine aminotransferase and aspartate aminotransferase levels, absence of histopathological organ changes, and IL-6 and tumor necrosis factor-alpha (TNF-α) plasma concentrations within pre-specified thresholds in preclinical models, supporting the potential application of these systems in mRNA vaccines, immunomodulatory therapies, and combination treatment therapies. Although challenges related to large-scale manufacturing, quality control, and regulatory approval remain, advances in membrane engineering and microfluidics technologies are accelerating their clinical translation.