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PreprintCC BY-NC-NDChemRxiv

Tailoring the Fusogenic Properties of cis-ssPalmO-phe Based Lipid Nanoparticles for mRNA Delivery

  • Anjana Barange1,2
  • Miteshkumar Moirangthem3,4
  • Meitram Niraj Luwang1,2
  • Santosh Kumar Meena3,4
4 affiliations
  1. 1Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory (NCL, Dr. Homi Bhabha Road, India, Pune-411008
  2. 2Academy of Scientific and Innovative Research (AcSIR
  3. 3Department of Chemical Engineering
  4. 4Indian Institute of Technology Ropar
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Abstract

Lipid nanoparticles (LNPs) are widely used for mRNA delivery, yet the effects of helper lipids on mixed bilayers containing redox-cleavable, self-degradable ionizable lipids remain unclear. Here, we conducted atomistic molecular dynamics simulations of bilayers formed from self-degradable lipid cis-ssPalmO-phe, examining 20 compositions with variations in helper-lipid headgroup (PC or PE), acyl chain length (C14-C24), and unsaturation, establishing structure-property relationships governing fusogenicity. We found that 40 mol% DOPC is optimal, with bilayer thickness of 4.60 nm and a diffusion rate of 0.37 ×10−7 cm2 s−1, balancing rigidity and dynamics for effective encapsulation and endosomal escape. PC bilayers are thinner (4.50 to 5.39 nm), more fluid, negatively charged (-0.21 to-2.59 V), enhancing stability and circulation. In contrast, PE bilayers are thicker (4.96 to 5.75 nm), denser, positively charged (up to +1.42 V), promoting curvature for endosomal fusion and cargo release. Higher unsaturation increases diffusion but decreases bilayer order, while saturated long-chain lipids maximize packing and binding energy indicating stability (up to-59.37 kcal mol−1). Tilt-angle analysis shows PC and PE adopt similar orientations and radial distribution functions confirm no clustering in saturated systems. These findings connect lipid chemistry to bilayer structure, offering design insights for degradable LNPs for mRNA and oligonucleotide therapies.

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Cite

BibTeXRIS
BibTeX
@misc{barange2026tailoring,
  title = {{Tailoring the Fusogenic Properties of cis-ssPalmO-phe Based Lipid Nanoparticles for mRNA Delivery}},
  author = {Anjana Barange and Miteshkumar Moirangthem and Meitram Niraj Luwang and Santosh Kumar Meena},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15008485/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008485/v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Tailoring the Fusogenic Properties of cis-ssPalmO-phe Based Lipid Nanoparticles for mRNA Delivery
AU  - Anjana Barange
AU  - Miteshkumar Moirangthem
AU  - Meitram Niraj Luwang
AU  - Santosh Kumar Meena
PY  - 2026
DA  - 2026/09/08
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15008485/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008485/v1
AB  - Lipid nanoparticles (LNPs) are widely used for mRNA delivery, yet the effects of helper lipids on mixed bilayers containing redox-cleavable, self-degradable ionizable lipids remain unclear. Here, we conducted atomistic molecular dynamics simulations of bilayers formed from self-degradable lipid cis-ssPalmO-phe, examining 20 compositions with variations in helper-lipid headgroup (PC or PE), acyl chain length (C14-C24), and unsaturation, establishing structure-property relationships governing fusogenicity. We found that 40 mol% DOPC is optimal, with bilayer thickness of 4.60 nm and a diffusion rate of 0.37 ×10−7 cm2 s−1, balancing rigidity and dynamics for effective encapsulation and endosomal escape. PC bilayers are thinner (4.50 to 5.39 nm), more fluid, negatively charged (-0.21 to-2.59 V), enhancing stability and circulation. In contrast, PE bilayers are thicker (4.96 to 5.75 nm), denser, positively charged (up to +1.42 V), promoting curvature for endosomal fusion and cargo release. Higher unsaturation increases diffusion but decreases bilayer order, while saturated long-chain lipids maximize packing and binding energy indicating stability (up to-59.37 kcal mol−1). Tilt-angle analysis shows PC and PE adopt similar orientations and radial distribution functions confirm no clustering in saturated systems. These findings connect lipid chemistry to bilayer structure, offering design insights for degradable LNPs for mRNA and oligonucleotide therapies.
ER  -