Biomedical Analysis · Published 2026-06-01 · DOI 10.1016/j.bioana.2026.05.003
Maosong Yang, Jiheng Wang, Chang Chen, Yang Liu
Biomacromolecules—including proteins, nucleic acids, and gene-editing tools—have demonstrated immense potential for therapeutic applications. However, their intracellular bioavailability is severely constrained by the cell membrane, which acts as a natural barrier to macromolecular entry. Conventional endocytic uptake pathways often lead to cargo entrapment within endosomes or lysosomes, followed by enzymatic degradation and consequently inefficient endosomal escape. To overcome this limitation, non-endocytic transmembrane delivery strategies have emerged as a compelling alternative. This review provides a systematic overview of recent advances in this field, with a particular emphasis on direct cytosolic delivery mechanisms, including physical membrane poration, cell-penetrating peptides (CPPs), membrane fusion, phase-separated carriers, virus-like particles (VLPs), and biological machines. By circumventing endosomal sequestration, these approaches enable the direct delivery of functional biomacromolecules into the cytosol, thereby offering innovative solutions for both therapeutic delivery and cellular engineering.
Abstract from DOAJ. Public domain (CC0 1.0).
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Yang, M., Wang, J., Chen, C., et al. (2026). Progress in non-endocytic dependent transmembrane delivery of biological macromolecules. Biomedical Analysis. https://doi.org/10.1016/j.bioana.2026.05.003