endosomaldisruptive

Endosomaldisruptive, a term sometimes used to describe strategies or materials that disrupt endosomal membranes to release cargo into the cytosol, is a key concept in intracellular delivery. It encompasses approaches that enable nucleic acids, proteins, and other therapeutic cargos to bypass endosomal entrapment after cellular uptake.

Mechanisms include pH-triggered membrane destabilization by ionizable lipids and pH-responsive polymers, the proton sponge effect from buffering polymers, fusogenic peptides and lipids that promote membrane fusion or pore formation, and photochemical internalization that uses light-activated agents to disrupt endosomes. These mechanisms aim to convert endosomal confinement into cytosolic accessibility while minimizing damage to the cell.

Applications include delivery of siRNA, mRNA, DNA, and proteins in gene therapy and vaccines, as well as intracellularly active drugs. Lipid nanoparticles and certain polymeric carriers rely on endosomaldisruptive processes for cytosolic delivery, while researchers seek to improve efficiency while mitigating toxicity. The concept underpins a broad range of therapeutic platforms, from basic research tools to clinically advanced formulations.

Challenges include achieving efficient escape across diverse cell types, avoiding excessive endosomal damage and cytotoxicity, and ensuring safety and reproducibility in clinical contexts. Ongoing work focuses on designing selective, tunable endosomaldisruptive agents with better tissue targeting and reduced off-target effects, as well as understanding cell-type–specific endosomal dynamics to optimize delivery outcomes.