Machine learning-assisted design of immunomodulatory lipid nanoparticles for delivery of mRNA to repolarize hyperactivated microglia DOI Creative Commons
Mehrnoosh Rafiei, Akbar Shojaei, Ying Chau

и другие.

Drug Delivery, Год журнала: 2025, Номер 32(1)

Опубликована: Март 3, 2025

Regulating inflammatory microglia presents a promising strategy for treating neurodegenerative and autoimmune disorders, yet effective therapeutic agents delivery to these cells remains challenge. This study investigates modified lipid nanoparticles (LNP) mRNA hyperactivated microglia, particularly those with pro-inflammatory characteristics, utilizing supervised machine learning (ML) classifiers. We developed screened library of 216 LNP formulations varying compositions, N/P ratios, hyaluronic acid (HA) modifications. The transfection efficiency eGFP was assessed in the BV-2 murine cell line under different immunological states, including resting activated conditions (LPS-activated IL4/IL13-activated). ML-guided morphometric analysis tracked phenotypes various subtypes before after transfection. Four ML classifiers were investigated predict phenotypic changes based on design parameters. Multi-Layer Perceptron (MLP) neural network emerged as best-performing model, achieving weighted F1-scores ≥0.8. While it accurately predicted responses from LPS-activated cells, struggled IL4/IL13-activated cells. MLP model validated by predicting performance four unseen delivering BV2 HA-LNP2 optimal formulation target IL10 mRNA, effectively suppressing phenotypes, evidenced shifts morphology, increased expression, reduced TNF-α levels. also evaluated human iPSC-derived confirming its efficacy modulating responses. highlights potential tailored techniques enhance therapy neuroinflammatory disorders leveraging carrier's immunogenic properties modulate microglial

Язык: Английский

mRNA-based vaccines and therapeutics: an in-depth survey of current and upcoming clinical applications DOI Creative Commons
Yu‐Shiuan Wang,

Monika Kumari,

Guanhong Chen

и другие.

Journal of Biomedical Science, Год журнала: 2023, Номер 30(1)

Опубликована: Окт. 7, 2023

mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely delivering the bioactive agents with high efficiency and without activating immune system. With regard mRNA vaccines, researchers modified structure enhance its stability promote systemic tolerance of antigenic presentation non-inflammatory contexts. Still, delivery naked mRNAs is inefficient results low levels antigen protein production. As such, lipid nanoparticles been utilized improve protect cargo from extracellular degradation. This advance was milestone development vaccines dispelled skepticism about technology yield clinically approved medicines. Following resounding success COVID-19, many other proposed treatment variety diseases. review begins discussion modifications vehicles, well factors that influence administration routes. Then, we summarize applications discuss further key points pertaining preclinical targeting wide range Finally, latest market trends future drugs.

Язык: Английский

Процитировано

80
Strategies to reduce the risks of mRNA drug and vaccine toxicity DOI
Dimitrios Bitounis, Eric Jacquinet, Maximillian A. Rogers

и другие.

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(4), С. 281 - 300

Опубликована: Янв. 23, 2024

Язык: Английский

Процитировано

74
From structural design to delivery: mRNA therapeutics for cancer immunotherapy DOI Creative Commons
Feng Zhou, Lujia Huang,

Shiqin Li

и другие.

Exploration, Год журнала: 2023, Номер 4(2)

Опубликована: Ноя. 17, 2023

Abstract mRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority expressing all sequence‐known proteins vivo. In particular, a small dosage of delivered mRNA, antigen‐presenting cells (APCs) can synthesize mutant neo‐antigens and multi‐antigens present epitopes to T lymphocytes elicit antitumor effects. addition, receptors like chimeric antigen receptor (CAR), T‐cell (TCR), CD134, immune‐modulating factors including cytokines, interferons, antibodies specific enhance immunological response against tumors. With the maturation vitro transcription (IVT) technology, large‐scale pure encoding be synthesized quickly. However, clinical translation mRNA‐based anticancer strategies is restricted by delivering into target organs or inadequate endosomal escape efficiency mRNA. Recently, there been some advances immunotherapy, which roughly classified modifications structure development delivery systems, especially lipid nanoparticle platforms. this review, latest overcoming limitations immunotherapies recent are summarized. Challenges opportunities applications also discussed.

Язык: Английский

Процитировано

55
Biomaterials for in situ cell therapy DOI Creative Commons
Chang Wang, Siyu Wang,

Diana D. Kang

и другие.

BMEMat, Год журнала: 2023, Номер 1(3)

Опубликована: Июль 19, 2023

Abstract Cell therapy has revolutionized the treatment of various diseases, such as cancers, genetic disorders, and autoimmune diseases. Currently, most cell products rely on ex vivo engineering, which requires sophisticated manufacturing processes poses safety concerns. The implementation in situ holds potential to overcome current limitations provides a broad range applications clinical feasibility future. A variety biomaterials have been developed improve function target delivery specific types due their excellent biocompatibility, tunable properties, other functionalities, provide reliable method achieve modulation reprogramming. In this article, we summarize recent advances for including T cells, macrophages, dendritic stem cells reprogramming leveraging lipid nanoparticles, polymers, inorganic materials, biomaterials. Finally, discuss challenges future perspectives therapy.

Язык: Английский

Процитировано

47
Lipid carriers for mRNA delivery DOI Creative Commons
Wanting Zhang,

Yuxin Jiang,

Yonglong He

и другие.

Acta Pharmaceutica Sinica B, Год журнала: 2022, Номер 13(10), С. 4105 - 4126

Опубликована: Ноя. 30, 2022

Messenger RNA (mRNA) is the template for protein biosynthesis and emerging as an essential active molecule to combat various diseases, including viral infection cancer. Especially, mRNA-based vaccines, a new type of vaccine, have played leading role in fighting against current global pandemic COVID-19. However, inherent drawbacks, large size, negative charge, instability, hinder its use therapeutic agent. Lipid carriers are distinguishable promising vehicles mRNA delivery, owning capacity encapsulate deliver negatively charged drugs targeted tissues release cargoes at desired time. Here, we first summarized structure properties different lipid carriers, such liposomes, liposome-like nanoparticles, solid lipid-polymer hybrid nanoemulsions, exosomes lipoprotein particles, their applications delivering mRNA. Then, development lipid-based formulations vaccine delivery systems was discussed highlighted. Recent advancements COVID-19 were emphasized. Finally, described our future vision perspectives this field.

Язык: Английский

Процитировано

70
mRNA Cancer Vaccines: Construction and Boosting Strategies DOI
Xiaoqing Liu, Pei Huang, Rusen Yang

и другие.

ACS Nano, Год журнала: 2023, Номер 17(20), С. 19550 - 19580

Опубликована: Окт. 11, 2023

In late 2020, the U.S. Food and Drug Administration (FDA) approved a lipid-based mRNA vaccine for prevention of COVID-19, which has pushed this field to be more closely studied motivated researchers delve deeper into therapeutics. To date, research on cancer vaccines been developed rapidly, substantial hopeful therapeutic results have achieved against various solid tumors in clinical trials. review, we first introduce three main components vaccines, including antigens, adjuvants, delivery vectors. Engineering these can optimize effects vaccines. For instance, appropriate modification structure alleviate poor stability innate immunogenicity mRNA, use vectors address issues low efficiency vivo. Second, emphatically discuss some strategies further improve efficacy namely modulating immunosuppressive tumor environment, optimizing administration routes, achieving targeting intended tissues or organs, employing combination therapy. These strengthen inhibitory ability increase possibility elimination. Finally, point out challenges practice offer our perspectives future developments rapidly evolving field. It is anticipated that will therapy near future.

Язык: Английский

Процитировано

44
Chemically engineering cells for precision medicine DOI
Yixin Wang, Zhaoting Li,

Fanyi Mo

и другие.

Chemical Society Reviews, Год журнала: 2023, Номер 52(3), С. 1068 - 1102

Опубликована: Янв. 1, 2023

This review summarizes chemical tools for cell engineering, introduces their wide application in diagnosis and therapy, discusses the challenges opportunities precision medicine.

Язык: Английский

Процитировано

42
Hydrogel armed with Bmp2 mRNA-enriched exosomes enhances bone regeneration DOI Creative Commons

Zhujun Yang,

Xuejian Li, Xueqi Gan

и другие.

Journal of Nanobiotechnology, Год журнала: 2023, Номер 21(1)

Опубликована: Апрель 5, 2023

Sustained release of bioactive BMP2 (bone morphogenetic protein-2) is important for bone regeneration, while the intrinsic short half-life at protein level cannot meet clinical need. In this study, we aimed to design Bmp2 mRNA-enriched engineered exosomes, which were then loaded into specific hydrogel achieve sustained more efficient and safe regeneration.Bmp2 mRNA was enriched exosomes by selective inhibition translation in donor cells, NoBody (non-annotated P-body dissociating polypeptide, a that inhibits translation) modified plasmids co-transfected. The derived named ExoBMP2+NoBody. vitro experiments confirmed ExoBMP2+NoBody had higher abundance thus stronger osteogenic induction capacity. When GelMA via ally-L-glycine CP05 linker, could be slowly released ensure prolonged effect when endocytosed recipient cells. vivo calvarial defect model, ExoBMP2+NoBody-loaded displayed great capacity promoting regeneration.Together, proposed can provide an innovative strategy regeneration.

Язык: Английский

Процитировано

37
A preparation method for mRNA-LNPs with improved properties DOI
Cong Geng,

Ke-fan Zhou,

Ying Yan

и другие.

Journal of Controlled Release, Год журнала: 2023, Номер 364, С. 632 - 643

Опубликована: Ноя. 16, 2023

Язык: Английский

Процитировано

31
Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications DOI Creative Commons
Yingying Shi,

Miaoyuan Shi,

Yì Wáng

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Ноя. 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.

Язык: Английский

Процитировано

17