Loop-Structured PEG-Lipoconjugate Enhances siRNA Delivery Mediated by Liner-PEG Containing Liposomes
Daniil V Gladkikh1, Elena V Shmendel2, Darya M Makarova2
1Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, 630090 Novosibirsk, Russia.
Molecules (Basel, Switzerland)
|October 29, 2025
Summary
Designing effective small interfering RNA (siRNA) delivery systems is crucial. This study shows that lipoconjugate structure, specifically the diP1500 with two anchor groups, significantly improves siRNA delivery by maintaining particle size and charge.
Area of Science:
- Biotechnology
- Nanomedicine
- Drug Delivery Systems
Background:
- Small interfering RNA (siRNA) therapeutics hold promise for treating various diseases.
- Effective delivery of siRNA to target cells remains a significant hurdle in therapeutic development.
- Liposomal formulations are being explored for enhanced siRNA delivery.
Purpose of the Study:
- To investigate the impact of targeted (folate-conjugated, F13) and shield lipoconjugates (P1500, diP1500) on siRNA delivery using cationic liposomes.
- To evaluate the influence of lipoconjugate structure (one vs. two anchor groups) on liposome characteristics and in vitro/in vivo siRNA delivery.
- To provide insights for rational design of targeted liposomal siRNA delivery systems.
Main Methods:
- Formulation of cationic liposomes using the 2X3-DOPE system with varying folate-conjugated (F13) and shield lipoconjugates (P1500, diP1500).
- Characterization of liposome particle size, surface charge, and stability at different N/P ratios.
- In vitro assessment of siRNA delivery, including receptor-mediated uptake via competitive inhibition assays.
- In vivo biodistribution studies to evaluate plasma circulation times and delivery efficiency.
Main Results:
- The F13/diP1500 lipoconjugate maintained optimal particle size (126.0 ± 23.0 nm) and preserved positive surface charges (21.6-30.5 mV), avoiding the "PEG dilemma".
- In contrast, F13/P1500 liposomes exhibited larger particle size (241.8 ± 65.7 nm) and significant charge neutralization (3.9-9.1 mV).
- Folate-mediated cellular uptake was confirmed, and in vivo studies showed superior plasma circulation for DSPE-PEG2000/diP1500 (1.84 ± 0.01 pmol/mL at 15 min).
Conclusions:
- The structure of PEG lipoconjugates, particularly the presence of two anchor groups (diP1500), is critical for effective siRNA delivery.
- Optimized lipoconjugate design balances targeting functionality (folate) and shielding (PEG) for improved liposome characteristics and therapeutic efficacy.
- These findings offer valuable guidance for the rational design of advanced targeted liposomal siRNA delivery systems.
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