Nanocarriers for cutting-edge cancer immunotherapies DOI Creative Commons
Joyce Hu, Pooria Mohammadi Arvejeh,

S Bone

et al.

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 15, 2025

Cancer immunotherapy aims to harness the body's own immune system for effective and long-lasting elimination of malignant neoplastic tissues. Owing advance in understanding cancer pathology immunology, many novel strategies enhancing immunological responses against various cancers have been successfully developed, some translated into excellent clinical outcomes. As one promising strategy next generation immunotherapies, activating multi-cellular network (MCN) within tumor microenvironment (TME) deploy multiple mechanisms action (MOAs) has attracted significant attention. To achieve this effectively safely, delivering or pleiotropic therapeutic cargoes targeted sites cancerous tissues, cells, intracellular organelles is critical, which numerous nanocarriers developed leveraged. In review, we first introduce payloads categorized according their predicted functions physicochemical structures forms. Then, nanocarriers, along with unique characteristics, properties, advantages, limitations, are introduced notable recent applications immunotherapy. Following discussions on targeting strategies, a summary each nanocarrier matching suitable provided comprehensive background information designing regimens.

Language: Английский

Multiarm-Assisted Design of Dendron-like Degradable Ionizable Lipids Facilitates Systemic mRNA Delivery to the Spleen DOI
Lulu Xue,

Xinhong Xiong,

Gan Zhao

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Lipid nanoparticles (LNPs) have emerged as pivotal vehicles for messenger RNA (mRNA) delivery to hepatocytes upon systemic administration and antigen-presenting cells following intramuscular injection. However, achieving mRNA non-hepatocytes remains challenging without the incorporation of targeting ligands such antibodies, peptides, or small molecules. Inspired by comb-like polymeric architecture, here we utilized a multiarm-assisted design construct library 270 dendron-like degradable ionizable lipids altering structures amine heads multiarmed tails optimal delivery. Following in vitro high-throughput screening, series top-dendron-like LNPs with high transfection efficacy were identified. These facilitated greater spleen vivo compared lipid analogs lacking structure. Proteomic analysis corona-LNP pellets showed enhancement key protein clusters, suggesting potential endogenous spleen. A lead LNP formulation, 18-2-9b2, was further used encapsulate Cre demonstrated excellent genome modification splenic macrophages, outperforming spleen-tropic MC3/18PA Ai14 mice model. Moreover, 18-2-9b2 encapsulating therapeutic BTB domain CNC homologue 1 (BACH1) exhibited proficient BACH1 expression subsequent Spic downregulation red pulp macrophages (RPM) Spic-GFP transgene model intravenous administration. results underscore facilitatem potentially opening avenues range mRNA-LNP applications, including regenerative medicine, replacement, gene editing therapies.

Language: Английский

Citations

3
Modular Design of Lipopeptide‐Based Organ‐Specific Targeting (POST) Lipid Nanoparticles for Highly Efficient RNA Delivery DOI Open Access

Chuanmei Tang,

Yexi Zhang,

Bowen Li

et al.

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 9, 2025

Lipid nanoparticles (LNPs) with highly efficient and specific extrahepatic targeting abilities are promising in gene delivery, the lipopeptides (LPs) excellent designability functionality expected to empower construction of functional LNPs. This study aims develop ionizable components that accurately match different lipid systems through modular design LPs. Based on this, a lipopeptide-based organ-specific (POST) LNP screening strategy is constructed, which lysine-histidine-based (KH-LPs) designed as components. The optimal KH-LP screened vitro shows siRNA/mRNA transfecting ability various hard-to-transfect cell lines. Compared classic LNPs, POST LNPs vivo achieve even higher (or at least comparable) efficiency specificity delivering mRNA siRNA lung, liver, spleen, respectively. structure-activity relationship (SAR) proves regulation LP structures can provide for systems, demonstrating potential this developing selective open up more possibilities therapy.

Language: Английский

Citations

1
Targeted Delivery of mRNA with Polymer–Lipid Nanoparticles for In Vivo Base Editing DOI

Qimingxing Chen,

Yan Chang,

Xiaoyan He

et al.

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Messenger RNA (mRNA) encoding base editors, along with single guide RNAs (sgRNAs), have emerged as a promising therapeutic approach for various disorders. However, there is still insufficient exploration in achieving targeted and efficient delivery of mRNA sgRNA to multiple organs while ensuring high biocompatibility stability vivo. To address this challenge, we synthesized library 108 poly(β-amino) esters (PBAEs) by incorporating 100% hydrophobic side chains end-caps varying amines. These PBAEs were further formulated other excipients, including helper lipids, cholesterol, PEGylated form polymer–lipid nanoparticles (PLNPs). Structure–function analysis revealed that eLog P could serve predictive parameter determining the liver or lung tropism PLNPs. The end-capped monoamines was significantly higher compared those diamines. Leveraging these findings, expanded PBAE identified leading (7C8C8) efficiency outperforming current FDA-approved ionizable lipids (ALC-0315, SM-102, Dlin-MC3-DMA). LD50 empty PLNPs determined be 403.8 ± 49.46 mg/kg, indicating safety profile. Additionally, demonstrated sustained transfection activity at least 2 months when stored −20 °C after freezing 4 following lyophilization. Subsequently, vivo editing using achieved an impressive approximately 70% significant reduction protein levels exceeding 90%. Notably, synergistic effects observed through simultaneous disruption proprotein convertase subtilisin/kexin type 9 angiopoietin-like 3 genes, resulting low-density lipoprotein cholesterol over 60% several months. compelling findings provide strong support development platforms mRNA-based therapies.

Language: Английский

Citations

1
Lung‐Specific mRNA Delivery by Ionizable Lipids with Defined Structure‐Function Relationship and Unique Protein Corona Feature DOI Creative Commons
Xiaoyan He, Rui Wang,

Yan Cao

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 18, 2025

Abstract Targeted delivery of mRNA with lipid nanoparticles (LNPs) holds great potential for treating pulmonary diseases. However, the lack rational design principles efficient lung‐homing lipids hinders prevalence therapeutics in this organ. Herein, combinatorial screening structure‐function analysis is applied to rationalize strategy nonpermanently charged lung‐targeted ionizable lipids. It discovered that carrying N‐methyl and secondary amine groups heads, three tails originated from epoxyalkanes, exhibiting superior selectivity efficiency. Representative systematically variation chemical structures are selected study well‐known but still puzzling “protein corona” adsorbed on surface LNPs. In addition commonly used corona‐biomarker vitronectin, other arginine‐glycine‐aspartic acid (RGD)‐rich proteins usually involved collagen‐containing extracellular matrix, such as fibrinogen fibronectin have also been identified a strong correlation lung tropism. This work provides insight into lung‐targeting reveals previously unreported function RGD‐rich protein corona

Language: Английский

Citations

1
Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications DOI Creative Commons
Yingying Shi,

Miaoyuan Shi,

Yì Wáng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 14, 2024

Abstract In the last decade, messenger ribonucleic acid (mRNA)-based drugs have gained great interest in both immunotherapy and non-immunogenic applications. This surge can be largely attributed to demonstration of distinct advantages offered by various mRNA molecules, alongside rapid advancements nucleic delivery systems. It is noteworthy that immunogenicity presents a double-edged sword. context immunotherapy, extra supplementation adjuvant generally required for induction robust immune responses. Conversely, non-immunotherapeutic scenarios, activation unwanted considering host tolerability high expression demand mRNA-encoded functional proteins. Herein, mainly focused on linear non-replicating mRNA, we overview preclinical clinical progress prospects medicines encompassing vaccines other therapeutics. We also highlight importance focusing host-specific variations, including age, gender, pathological condition, concurrent medication individual patient, maximized efficacy safety upon administration. Furthermore, deliberate potential challenges may encounter realm disease treatment, current endeavors improvement, as well application future advancements. Overall, this review aims present comprehensive understanding mRNA-based therapies while illuminating prospective development drugs.

Language: Английский

Citations

6
Principles of lipid nanoparticle design for mRNA delivery DOI Creative Commons
Yiran Zhang, Xinyue Zhang, Yongsheng Gao

et al.

BMEMat, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

Abstract mRNA therapeutics have significantly evolved within the life sciences, particularly in applications such as vaccines, tumor immunotherapy, protein replacement, gene editing, and monoclonal antibody therapy. To fully realize potential of drugs mitigate adverse effects, substantial vector materials been developed for delivery these pharmaceutical agents. Lipid nanoparticles (LNPs) represent most clinically advanced carriers, recognized by U.S. Food Drug Administration approved vaccines numerous clinical trials. Diverse therapeutic necessitate tailored design LNPs. Herein, we outline principles LNP delivery, focusing specifically on their effectiveness, targeting capabilities, safety profiles, nanoparticle stability. Additionally, present latest advancements mRNA‐LNP technology. This review aims to elucidate benefits systems therapeutics, providing insights into breakthroughs innovative ideas further enhancing advantages. These summaries are dedicated promoting broader LNP‐mRNA drugs, aiming advance treatment serious diseases an effective safe manner.

Language: Английский

Citations

5
Ionizable Cholesterol Analogs as the Fifth Component of Lipid Nanoparticles for Selective Targeting Delivery of mRNA DOI
Chao Liu, Yuhao Jiang,

Wenliang Xue

et al.

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Lipid nanoparticles (LNP) have shown great promise in clinical applications for delivering mRNA. Targeted delivery of mRNA to particular tissues or organs is essential precise therapeutic outcomes and minimized side effects various disease models. However, achieving targeted beyond the liver a challenge based on current LNP formulations. In this report, we synthesized four ionizable cholesterol analogs by attaching two tertiary amine groups onto head cholesterol-like structure incorporated them as fifth component into conventional commercial LNPs ALC-0315 SM-102. Selective targeting achieved adjusting proportion LNP. Specifically, spleen-targeted 0315-Ergo-40% formulation demonstrated an impressive 95% efficiency, while lung-targeted 102-Sito-40% up 78%. Moreover, when strategy applied self-developed lipid named U-101 instead SM-102, efficiencies spleen lungs reach 96 71%, respectively. Multiple assessments suggest that inclusion does not compromise stability, indicated consistent particle size, polydispersity index (PDI), encapsulation efficiency. Furthermore, test results kidney function immunogenicity reveal no increase toxicity vivo following introduction component. Additional studies vitro cytotoxicity, lysosomal escape, cellular transfection efficiency confirm diminish performance. Taken together, incorporation leads delivery, which features strong organ selectivity, high safety, suitability further evaluation.

Language: Английский

Citations

0
Ether bond-modified lipid nanoparticles for enhancing the treatment effect of hepatic fibrosis DOI
Runxuan Chu, Jianglong Kong, Qiang Gao

et al.

International Journal of Pharmaceutics, Journal Year: 2025, Volume and Issue: 671, P. 125192 - 125192

Published: Jan. 16, 2025

Language: Английский

Citations

0
Intracellular trafficking of lipid nanoparticles is hindered by cholesterol DOI Creative Commons
Ceng Luo, Yunfei Li, Haidong Liu

et al.

International Journal of Pharmaceutics, Journal Year: 2025, Volume and Issue: 671, P. 125240 - 125240

Published: Jan. 17, 2025

Language: Английский

Citations

0
Intelligent Design of Lipid Nanoparticles for Enhanced Gene Therapeutics DOI Creative Commons
Yichen Yuan, Ying Li, Guo Li

et al.

Molecular Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Lipid nanoparticles (LNPs) are an effective delivery system for gene therapeutics. By optimizing their formulation, the physiochemical properties of LNPs can be tailored to improve tissue penetration, cellular uptake, and precise targeting. The application these targeted strategies within LNP framework ensures efficient therapeutic agents specific organs or cell types, thereby maximizing efficacy. In realm genome editing, have emerged as a potent vehicle delivering CRISPR/Cas components, offering significant advantages such high in vivo incorporation machine learning into optimization platforms therapeutics represents advancement, harnessing its predictive capabilities substantially accelerate research development process. This review highlights dynamic evolution technology, which is expected drive transformative progress field therapy.

Language: Английский

Citations

0