Direct cytosolic delivery of DNA by creating fast closable holes in the cell membrane

Delivering exogenous compounds into cells in vitro or in vivo is a critical yet very challenging step in gene-and cell-based therapies, biomanufacturing, and basic research. Although several nanotechnologies could highly facilitate exogenous compounds into the target cell, they are typically internalized by cells into membrane-bounded endosomes, and most of them are trapped in these endosomes and degraded by endosomes, failing to access the cytosolic cell machinery. Here, we have prepared a copolymer that could target and create fast closable holes in the cell membrane, via which the exogenous genes in nanoparticles can be directly delivered into the cell cytosol, highly bypassing the severe endosome trapping of normal delivery approaches and achieving high gene transfection. Moreover, in cells, the copolymer undergoes fast deboronation to release the absorbed lipid for fast repair of the holes. This cell membrane hole-creating copolymer would provide a very promising means for delivering functional nanoparticles, DNA, RNA, and proteins directly into the cell cytosol, avoiding cargo entrapment in endosomes and maintaining cargo functionality after delivery.