24:T4b5,As the most advanced non-viral delivery system, lipid nanoparticles (LNPs) were approved by the FDA, propelling the advancements of gene therapy. However, their clinical applications are hampered by the potential immunogenicity of the lipid components that trigger immune-related adverse events, like inflammation and allergy. Herein, we formulate various dLNPs with diminished immunogenicity by incorporating dexamethasone (Dex) into liver-, spleen-, and lung-targeting LNPs formulations that exhibit excellent abilities to target specific organs and deliver various types of RNA, such as mRNA and siRNA. In vivo investigations demonstrate unparalleled advantages in safety as compared to conventional LNPs, showing promising potential in the development of RNA therapeutics. Intriguingly, the encapsulation of runt-related transcription factor-1 siRNA (siRUNX1) into lung-targeting dLNPs (dLNPs@siRUNX1) demonstrates remarkable advantages in the treatment of pulmonary fibrosis through the synergy of gene therapy and drug therapy. This research establishes secure and universal platforms for the precise delivery of nucleic acid therapeutics, showcasing promising clinical applications in gene therapy.25:T53b,Interleukin-2 (IL-2) is a cytokine vital for CD8⁺ T cell activation and proliferation, holding great potential for cancer immunotherapy. Nevertheless, inherent shortcomings of short half-life, activation of regulatory T (T_reg) cells, and systemic toxicity limit its application. To tackle these, a circular RNA (cRNA)-based IL-2 therapy using immunomodulatory lipid nanoparticles [ursodeoxycholic acid lipid nanoparticles (ULNPs)] and sustained-release hydrogel was developed. Fusing fragment crystallizable (Fc) region into IL-2 and encoding this fusion protein IL-2-Fc (IL-2F) in cRNA (cRNA^IL-2F) greatly extend the half-life. ULNPs containing ursodeoxycholic acid, a transforming growth factor-β1 inhibitor, suppress the function of T_reg cells. Consequently, the ULNPs-cRNA^IL-2F formulation promotes CD8⁺ T cells and suppresses T_reg cells, increasing the CD8⁺/T_reg ratio for effective immunotherapy. Furthermore, a locally administrated hydrogel loading with ULNPs-cRNA^IL-2F sustains the release, enhancing efficacy and reducing toxicity. This innovative approach achieves remarkable tumor inhibition in both melanoma and orthotopic glioma models with or without surgery, offering a promising future for cancer immunotherapy.26:T4ae,Abstract Insufficient accumulation of lipid nanoparticles (LNPs)‐based mRNA vaccines in antigen presenting cells remains a key barrier to eliciting potent antitumor immune responses. Herein, we develop dendritic cells (DCs) targeting LNPs by taking advantage of mannose receptor‐mediated endocytosis. Efficient delivery of mRNA to DCs is achieved in vitro and in vivo utilizing the sweet LNPs (STLNPs‐Man). Intramuscular injection of mRNA vaccine (STLNPs‐Man@mRNA OVA ) results in a four‐fold higher uptake by DCs in comparison with commercially used LNPs. Benefiting from its DCs targeting ability, STLNPs‐Man@mRNA OVA significantly promotes the antitumor performances, showing a comparable therapeutic efficacy by using one‐fifth of the injection dosage as the vaccine prepared from normal LNPs, thus remarkably avoiding the side effects brought by conventional mRNA vaccines. More intriguingly, STLNPs‐Man@mRNA OVA exhibits the ability to downregulate the expression of cytotoxic T‐lymphocyte‐associated protein 4 on T cells due to the blockade of CD206/CD45 axis, showing brilliant potentials in promoting antitumor efficacy combined with immune checkpoint blockade therapy.

#	Concept	H-Index	Publications	Citations
1	Engineering	1	1	10
2	Medicine	1	1	10
3	Biomedical Engineering	1	1	10
4	Cell Biology	1	1	10
5	Immunology	1	1	10

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