Stimulus-Responsive Polymeric Carriers for Gene Delivery: Balancing Endosomal Escape with Nucleic Acid Release

Area of Science:

• Biomaterials Science
• Nanotechnology
• Drug Delivery

Background:

• Polymeric carriers for nucleic acid delivery must overcome endosomal escape and cytosolic release.
• These intracellular barriers are often optimized independently.

Purpose of the Study:

• This review highlights the coupled nature of endosomal escape and cargo release.
• It argues that a fundamental tradeoff exists due to shared electrostatic and pH-dependent interactions.

Main Methods:

• Analysis of major polymeric delivery strategies and their trigger mechanisms relative to endosomal escape.
• Assessment of assays for measuring escape and release.
• Evaluation of in vivo translational variables.

Main Results:

• pH-responsive polymers fail to decouple escape from binding.
• Charge-shifting and non-pH-responsive polymers offer orthogonal release but face alignment issues.
• Common failure modes include premature release and kinetic misalignment.
• In vitro assays do not capture in vivo complexities like protein corona and PEG shielding.

Conclusions:

• The escape-release tradeoff cannot be solved by chemistry alone.
• Resolution requires integrated design across spatial, temporal, and formulation axes.