Lipid nanoparticle-mediated RNA delivery holds great potential to treat various liver diseases. However, targeted delivery of RNA therapeutics to activated liver-resident fibroblasts for liver fibrosis treatment remains challenging. Here, we develop a combinatorial library of anisamide ligand-tethered lipidoids (AA-lipidoids) using a one-pot, two-step modular synthetic method and adopt a two-round screening strategy to identify AA-lipidoids with both high potency and selectivity to deliver RNA payloads to activated fibroblasts. The lead AA-lipidoid AA-T3A-C12 mediates greater RNA delivery and transfection of activated fibroblasts than its analog without anisamide and the FDA-approved MC3 ionizable lipid. In a preclinical model of liver fibrosis, AA-T3A-C12 enables ~65% silencing of heat shock protein 47, a therapeutic target primarily expressed by activated fibroblasts, which is 2-fold more potent than MC3, leading to significantly reduced collagen deposition and liver fibrosis. These results demonstrate the potential of AA-lipidoids for targeted RNA delivery to activated fibroblasts. Furthermore, these synthetic methods and screening strategies open a new avenue to develop and discover potent lipidoids with targeting properties, which can potentially enable RNA delivery to a range of cell and tissue types that are challenging to access using traditional lipid nanoparticle formulations.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9845313 | PMC |
| http://dx.doi.org/10.1038/s41467-022-35637-z | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity.
Am J Physiol Endocrinol Metab
January 2025
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97239.
Maternal obesity puts the offspring at high risk of developing obesity and cardio-metabolic diseases in adulthood. Here, we utilized a mouse model of maternal high-fat diet (HFD)-induced obesity that recapitulates metabolic perturbations seen in humans. We show increased adiposity in the offspring of HFD-fed mothers (Off-HFD) when compared to the offspring regular diet-fed mothers (Off-RD).
View Article and Find Full Text PDFInhalable siRNA Targeting IL-11 Nanoparticles Significantly Inhibit Bleomycin-Induced Pulmonary Fibrosis.
ACS Nano
January 2025
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
For idiopathic pulmonary fibrosis (IPF), interleukin 11 (IL-11) is a pivotal cytokine that stimulates the transformation of fibroblasts into myofibroblasts, thus accelerating the progression of pulmonary fibrosis. Here, we develop an innovative inhalable small interfering RNA (siRNA) delivery system termed PEI-GBZA, which demonstrates impressive efficiency in loading siIL-11 targeting IL-11 (siIL-11) and substantially suppresses the differentiation of fibroblasts into myofibroblasts and epithelial-mesenchymal transition (EMT), reduces neutrophil and macrophage recruitment, and ultimately relieves the established fibrotic lesions in the IPF model. PEI-GBZA is prepared by modifying low-molecular-weight polyethylenimine (PEI) with 4-guanidinobenzoic acid (GBZA).
View Article and Find Full Text PDFPhotochemical Stabilization of Self-Assembled Spherical Nucleic Acids.
Small
January 2025
Department of Chemistry, McGill University, 801, Sherbrooke St. West, Montreal, QC, H3A 0B8, Canada.
Oligonucleotide therapeutics, including antisense oligonucleotides and small interfering RNA, offer promising avenues for modulating the expression of disease-associated proteins. However, challenges such as nuclease degradation, poor cellular uptake, and unspecific targeting hinder their application. To overcome these obstacles, spherical nucleic acids have emerged as versatile tools for nucleic acid delivery in biomedical applications.
View Article and Find Full Text PDFA Smart mRNA-Initiated Theranostic Multi-shRNA Nanofactory for Precise and Efficient Cancer Gene Therapy.
Adv Healthc Mater
January 2025
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China.
Despite the significant potential of short hairpin RNA (shRNA)-mediated gene therapy for various diseases, the clinical success of cancer treatment remains poor, partly because of low selectivity and low efficiency. In this study, an mRNA-initiated autonomous multi-shRNA nanofactory (RNF@CM) is designed for in vivo amplification imaging and precise cancer treatment. The RNF@CM consists of a gold nanoparticle core, an interlayer of two types of three-stranded DNA/RNA hybrid probes, one of which is bound to aptamer-inhibited DNA polymerases, and an outer layer of the cancer cell membrane.
View Article and Find Full Text PDFCRISPR-Enabled Autonomous Transposable Element (CREATE) for RNA-based gene editing and delivery.
EMBO Rep
January 2025
Myeloid Therapeutics Inc., Cambridge, MA, 02139, USA.
To address a wide range of genetic diseases, genome editing tools that can achieve targeted delivery of large genes without causing double-strand breaks (DSBs) or requiring DNA templates are necessary. Here, we introduce CRISPR-Enabled Autonomous Transposable Element (CREATE), a genome editing system that combines the programmability and precision of CRISPR/Cas9 with the RNA-mediated gene insertion capabilities of the human LINE-1 (L1) element. CREATE employs a modified L1 mRNA to carry a payload gene, and a Cas9 nickase to facilitate targeted editing by L1-mediated reverse transcription and integration without relying on DSBs or DNA templates.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!