Recent advances of engineering cell membranes for nanomedicine delivery across the blood-brain barrier

Abstract

The blood-brain barrier (BBB) poses a major challenge to the effective delivery of therapeutic agents for the treatment of central nervous system (CNS) disorders. The integration of cell membrane engineering with nanotechnology has recently enabled the development of membrane-engineered nanoparticles (CNPs). These nanocarriers exhibit enhanced BBB penetration and improved CNS targeting. This review systematically summarizes the latest advances in the development and application of CNPs, emphasizing how different cellular sources-such as erythrocytes, platelets, tumor cells, and leukocytes-impact delivery efficiency and therapeutic outcomes. We also examine the molecular mechanisms underlying nanoparticle-BBB interactions and highlight the importance of biosafety evaluations. Moreover, critical barriers to clinical translation, including large-scale manufacturing challenges, batch-to-batch variability, and regulatory complexities, are discussed. Finally, we explore emerging strategies-particularly the integration of artificial intelligence (AI)-that hold potential for overcoming existing clinical gaps, enabling the rational design and optimized development of CNP-based therapeutics for CNS disorders. By integrating mechanistic insights with translational perspectives, this review provides a clear conceptual and technological foundation for the development of next-generation CNS-targeted nanotherapeutics.

Fig. 1

(A) Schematic illustration of the BBB structure. (B) Diagram depicting the passive transcytosis mechanisms of nanomedicines across the BBB. Abbreviations: TJ, tight junction. The image was created using BioRender.com and is used with permission

Fig. 2

Fabrication methods of cell membrane-coated nanoparticles (CNPs). Parent cells are first collected and subjected to membrane extraction. The isolated cell membranes are subsequently coated onto the nanoparticle (NP) core using one of three different techniques: physical extrusion, sonication, or microfluidic electroporation. The image was created using BioRender.com and is used with permission

Fig. 3

Development timeline of CNPs for BBB-crossing drug delivery. The image was created using BioRender.com and is used with permission

Fig. 4

(A) Schematic illustration of erythrocyte membrane-engineered nanoparticle (RBCNP) fabrication, illustrating the integration of various peptides onto the RBCNP surface. (B) Mechanisms of RBCNP-mediated BBB crossing, facilitated by peptide modifications and interactions with corresponding endothelial cell membrane receptors. RBCNPs have been utilized for the treatment of brain tumors and Alzheimer’s disease (AD). The image was created using BioRender.com and is used with permission

Fig. 5

(A) Schematic illustration of platelet membrane-coated nanoparticle (PCNP) fabrication. (B) Mechanisms of PCNP-mediated BBB crossing, facilitated by platelet membrane proteins interacting with corresponding endothelial cell membrane receptors or by peptide modifications enabling BBB penetration via adsorptive transcytosis. PCNPs have been utilized for the treatment of brain tumors and ischemic stroke. The image was created using BioRender.com and is used with permission

Fig. 6

(A) Schematic illustration of cancer cell membrane-coated nanoparticle (CCNP) fabrication. (B) Mechanisms of CCNP-mediated BBB crossing, facilitated by cancer cell membrane proteins interacting with corresponding endothelial cell membrane receptors. Interactions between cell membrane proteins contribute to the disruption of tight junctions (TJs). CCNPs have been utilized for brain tumor inhibition, image-guided PTT, and image-guided tumor resection. The image was created using BioRender.com and is used with permission

Fig. 7

(A) Schematic illustration of macrophage membrane-coated nanoparticle (MCNP) fabrication. (B) Mechanisms of MCNP-mediated BBB crossing, facilitated by macrophage membrane proteins or peptide modifications interacting with corresponding endothelial cell membrane receptors, lead to the disruption of tight junctions (TJs). MCNPs have been utilized for the treatment of brain tumors and Alzheimer’s disease (AD). The image was created using BioRender.com and is used with permission

Fig. 8

(A) Schematic illustration of neutrophil membrane-coated nanoparticle (NCNP) fabrication. (B) Mechanisms of NCNP-mediated BBB crossing, facilitated by neutrophil membrane proteins interacting with corresponding endothelial cell membrane receptors, lead to the disruption of tight junctions (TJs). NCNPs have been utilized for the treatment of ischemic stroke and brain tumors. The image was created using BioRender.com and is used with permission

Fig. 9

Artificial Intelligence (AI)-assisted strategies addressing clinical translation challenges of BBB-crossing CNPs. AI facilitates the efficient development of CNS-targeted CNPs by enabling parameter monitoring, peptide screening, nanotoxicity evaluation, and biodistribution prediction