image: Gemini surfactants improve transfection efficiency or biocompatibility through structural optimization, such as replacing the head group with imidazole or pyridine, using shorter spacers, incorporating longer hydrophobic tail chains, and modifying with small molecules, peptides, amino acids, and biomimetic strategies. Additionally, studies on the delivery mechanisms of Gemini surfactants, together with their future development strategies, have established a critical foundation for the advancement of gene therapy in disease treatment. AI, artificial intelligence; ER, endoplasmic reticulum; GS, Gemini surfactant; HCM, hepatocyte membrane; NA, nucleic acid; RBCM, red blood cell membrane.
Credit: Huali Chen
As gene therapy continues to make headlines with breakthroughs in cancer, genetic disorders and other major diseases, the race to deliver nucleic-acid therapeutics safely and efficiently is still the field’s biggest bottleneck. While viral vectors dominate clinical pipelines thanks to their high transfection efficiency, their Achilles’ heel—immunogenicity, complex manufacturing, safety risks and limited scalability—has opened the door for non-viral alternatives.
A team led by Prof. Huali Chen and Prof. Qianyu Zhang from Chongqing Medical University now offers a detailed roadmap for one of the intriguing newcomers for non-viral gene delivery vectors: Gemini surfactants. Published in MedComm – Future Medicine, their review is the first to knit together structural engineering tricks, smart functional add-ons and in vivo tracking data into a single, forward-looking blueprint for these double-headed, double-tailed carriers.
Gemini surfactants owe their name to the twin hydrophilic heads and hydrophobic tails that flank a flexible spacer. The review emphasizes that key structural elements—spacer length, hydrophobic tail length/saturation, and headgroup functionality (e.g., aromatic pyridine groups enabling π–π stacking and proton buffering)—directly govern their delivery performance and complex stability. But structure alone isn’t enough. The team catalogs next-gen upgrades: cancer-homing peptides (p18-4), retina-specific neuro-IGSF ligands, serine “stealth” tags for biocompatibility, and disulfide ethyl spacers that fall apart in the reductive cytosol. Biomimetic coatings derived from red-blood-cell or hepatocyte membranes have also been used to prolong circulation and lessen immune recognition. A crucial insight explored is the cellular journey of GS complexes. Instead of the classic “endosome-to-lysosome” dead end, many engineered Gemini carriers hijack caveolae-mediated uptake, zip along microtubules and dock at the endoplasmic reticulum—effectively a VIP lane that shields DNA from degradation and speeds nuclear entry.
GS-based systems show compelling potential across diverse disease models, including tumors, heart disease, hepatitis, glaucoma, enamel defects, and mucosal disorders. Despite this promise, the team highlights unresolved challenges essential for clinical success: clarifying the in vivo metabolic fate and long-term toxicity of GSs, and thoroughly evaluating their immunogenicity profile. To accelerate translation, the review proposes leveraging artificial intelligence-assisted design combined with high-throughput screening and structure-activity databases for targeted development of safer, more effective GS materials.
“We envision this review serving as a vital bridge linking molecular design to biological function, providing clear guidance for developing advanced GS-based non-viral delivery systems,” the team concludes.
See the article:
Recent Progress in Gene Delivery Systems Based on Gemini-Surfactant
https://doi.org/10.1002/mef2.70027
Article Title
Recent Progress in Gene Delivery Systems Based on Gemini-Surfactant
Article Publication Date
17-Jul-2025