Authorship：Lead author,　Corresponding author   Language：English   Publisher：Rsc Medicinal Chemistry  

Current LNP technology faces challenges that must be addressed to enhance the functionality of mRNA therapeutics. Recent studies show disulfide-conjugated molecules improve cell membrane permeability. Here, we investigated incorporating cyclic disulfide (CDL) units into lipid components of LNPs to enhance LNP-mRNA performance. A lipid library with branched and unbranched alkyl chains (C16-C20) and tertiary amine groups modified with CDLs was designed. While cellular uptake was unchanged, some mRNA-loaded LNPs with CDLs achieved more than 2-fold higher transfection efficiency than LNPs with MC3 or SM102 alone. Intracellular analysis revealed that the addition of CDL lipids significantly promoted endosomal escape. The CDL-incorporated LNPs administered subcutaneously in mice showed significantly higher luciferase gene expression compared to LNPs without CDL. Additionally, LNPs encapsulating OVA antigen-encoding mRNA induced a potent antitumor response against the EG7-OVA lymphoma model. These results suggest CDL modifications enhance LNP-based mRNA delivery, offering potential for broader therapeutic applications and improved clinical outcomes.

DOI： 10.1039/d5md00084j

Open Access

Web of Science

Scopus

PubMed

Publisher：Rsc Pharmaceutics  

Applying lipid nanoparticle (LNP) technology to ribonucleic acid (RNA) nanomedicines was integral to the success of mRNA vaccines against COVID-19. To expand the power of LNP technology, extrahepatic delivery systems have been developed using specific ligands that target the cells in question. However, recent increases in evidence support targeting without the need to attach specific ligands to nanocarriers. In this review, we focused on protein corona-mediated extrahepatic delivery of nanoparticles as an alternative to classic ligand-mediated active targeting. First, the interaction of LNPs with biological components and the impact that the physicochemical properties of LNPs exert on their biological fate are discussed. Then, we highlight a new system that targets activated hepatic stellate cells (aHSCs) as a successful model achieved through intensive optimization of LNPs based on an ionizable cationic lipid library. We also discuss cumulative evidence that support the ligand-free extrahepatic delivery of nanoparticles to a broad diversity of tissues, such as the spleen, lungs, brain, tumors, kidneys, placenta, pancreas, and bone marrow. In conclusion, we propose protein corona-mediated extrahepatic delivery as a new strategy of active targeting for RNA nanomedicines and inspire the future directions in this area.

DOI： 10.1039/d5pm00079c

Open Access

Web of Science

Scopus

Language：English   Publisher：Nature Biotechnology  

Correction to: Nature Biotechnologyhttps://doi.org/10.1038/s41587-025-02561-8, published online 19 February 2025. In the version of the article initially published, in Fig. 4b, the IVIS images for “IRES-circ” at 48 h and 72 h were duplicates of the “Cap-circ” images for the same time points due to an error in typesetting. Fig. 4b has now been corrected in the HTML and PDF versions of the article.

DOI： 10.1038/s41587-025-02758-x

Web of Science

Scopus

PubMed

Language：English   Publisher：Nature Biotechnology  

Circular mRNA faces challenges in enhancing its translation potential as an RNA therapeutic. Here we introduce two molecular designs that bolster circular mRNA translation through an internal cap-initiated mechanism. The first consists of a circular mRNA with a covalently attached N⁷-methylguanosine (m⁷G) cap through a branching structure (cap-circ mRNA). This modification allows circular mRNA to recruit translation machinery and produce proteins more efficiently than internal ribosome entry site (IRES)-containing circular mRNAs. Combining with an N¹-methylpseudouridine (m¹Ψ) modification, cap-circ mRNA exhibits a lower acute immunostimulatory effect, maintaining high translation in mice. The second design features the non-covalent attachment of an m⁷G cap to a circular mRNA through hybridization with an m⁷G cap-containing oligonucleotide, enhancing translation by more than 50-fold. This setup allows circular mRNAs to synthesize reporter proteins upon hybridizing with capped mRNAs or long non-coding RNAs and to undergo rolling circle-type translation. These advancements broaden the therapeutic applications of circular mRNAs by minimizing their molecular size, elevating translation efficiency and facilitating cell-type-selective translation.

DOI： 10.1038/s41587-025-02561-8

Web of Science

Scopus

PubMed

DOI： 10.26434/chemrxiv-2025-d7zzq

Event date： 2025.10

Presentation type：Oral presentation (invited, special)  

Event date： 2025.9

Language：English   Presentation type：Oral presentation (invited, special)  

Event date： 2025.7

Presentation type：Symposium, workshop panel (nominated)  

Event date： 2025.3

Presentation type：Oral presentation (general)  

Event date： 2024.7

Presentation type：Poster presentation