Cellular uptake: lessons from supramolecular organic chemistry

Area of Science:

• Supramolecular Organic Chemistry
• Chemical Biology
• Biotechnology

Background:

• Life sciences face persistent challenges in cellular uptake and delivery.
• Established and emerging principles of supramolecular organic chemistry offer innovative solutions.
• Dynamic covalent chemistry is a key area for addressing these biological problems.

Purpose of the Study:

• To highlight the importance of supramolecular organic chemistry principles for life science problems.
• To discuss dynamic covalent chemistry on cell surfaces, focusing on disulfide exchange.
• To explore applications in cell-penetrating peptides, gene transfection, and siRNA delivery.

Main Methods:

• Review of established and emerging supramolecular organic chemistry principles.
• Focus on dynamic covalent chemistry, including disulfide, boronate, and hydrazone exchange.
• Analysis of proximity effects, counterion hopping, ring tension, and ion pair-π interactions.

Main Results:

• Disulfide exchange on cell surfaces facilitates thiol-mediated uptake.
• Supramolecular chemistry explains phenomena like "arginine magic" and the "pyrenebutyrate trick."
• Emerging "disulfide magic" with cell-penetrating poly(disulfide)s shows promise.

Conclusions:

• Innovative chemistry is crucial for tackling complex biological challenges beyond incremental progress.
• Dynamic covalent chemistry on cell surfaces has broad applications in medicine and biotechnology.
• Supramolecular organic chemistry provides essential tools for advancing life sciences.