By Johnny Moseman / February 16, 2026
Engineering More Durable and Potent mRNA Nanoparticles for Vaccines and Cancer Therapy
Johns Hopkins University researchers have developed a simple post-assembly crosslinking strategy that stabilizes mRNA lipid nanoparticles (LNPs), enhancing both their delivery efficiency and stability during storage.
The new approach introduces reversible, acid-sensitive covalent crosslinks after LNP formation, reinforcing their structure during storage and lyophilization. Once the nanoparticles enter cells, the crosslinks loosen under mildly acidic intracellular conditions, enabling efficient mRNA release and functional delivery.
The findings were published today in Nature Chemical Engineering.
Using this method, the team screened more than 180 formulations and identified candidates that significantly outperformed conventional LNPs in mice, maintaining strong gene activity for several weeks. The researchers attribute the improved performance to enhanced endosomal escape and reduced compositional drift compared with conventional LNPs. Notably, these benefits were preserved even after freeze-drying, suggesting that crosslinking may ease the cold-chain requirements that currently limit mRNA therapeutics.
“As we continue to explore the full potential of mRNA technologies, improving the stability and efficiency of LNP platforms is essential,” said Hai-Quan Mao, director of the Institute for NanoBioTechnology and professor of materials science and engineering and biomedical engineering at Johns Hopkins University.
When used as vaccine carriers, the crosslinked LNPs elicited stronger antigen-specific CD8⁺ T-cell responses and higher IgG titers, leading to stronger tumor suppression in multiple mouse models of melanoma. These enhanced immune responses also improved control of tumors expressing clinically relevant antigens, highlighting the platform’s promise for cancer immunotherapy.
This modular chemistry can be applied to widely used LNP delivery systems and integrated into current LNP manufacturing workflows.
“This strategy could enable mRNA medicines that are more stable and easier to distribute, helping broaden access to advanced mRNA vaccines and therapies in resource-limited settings,” said Xiang Liu and Yining Zhu, INBT postdocs who led this study.
This team will next look to determine how crosslink density interacts with specific pathways and environments and by defining these cellular dependencies, more precise tuning for different therapeutics could be enabled.
