Principles of lipid nanoparticle design for mRNA delivery

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

---

Discovery of Ketal‐Ester Ionizable Lipid Nanoparticle with Reduced Hepatotoxicity, Enhanced Spleen Tropism for mRNA Vaccine Delivery

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 10, 2024

The safety and efficacy of the lipid nanoparticle (LNP) delivery system are crucial for successful development messenger RNA vaccines. We designed synthesized a series ketal ester lipids (KELs), featuring biodegradable moiety in linker segments tail. Through iterative optimization head tail groups KELs, we tuned pKa molecular shapes, identified (4S)-KEL12 as safe efficient ionizable mRNA delivery. LNP showed significantly higher lower toxicity than DLin-MC3-DMA LNP. In comparison to SM-102 LNP, exhibited better spleen tropism, reduced liver hepatotoxicity. Additionally, demonstrated good biodegradability following intramuscular or intravenous injection. Notably, encapsulated with therapeutic cancer vaccine elicited robust cellular immune responses leading substantial tumor regression along prolonged survival tumor-bearing mice. Our results suggest that holds great promise comprehensive analysis structure-activity relationship, toxicity, biodegradability, distribution, expression, efficacy, stereochemistry these LNPs will greatly contribute rational design discovery novel lipid-based systems.

Language: Английский

---

In situ engineering of mRNA-CAR T cells using spleen-targeted ionizable lipid nanoparticles to eliminate cancer cells

Nano Today, Journal Year: 2024, Volume and Issue: 59, P. 102518 - 102518

Published: Oct. 3, 2024

Language: Английский

---

Personalized mRNA vaccines in glioblastoma therapy: from rational design to clinical trials

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: Oct. 4, 2024

Abstract Glioblastomas (GBMs) are the most common and aggressive malignant brain tumors, presenting significant challenges for treatment due to their invasive nature localization in critical regions. Standard includes surgical resection followed by radiation adjuvant chemotherapy with temozolomide (TMZ). Recent advances immunotherapy, including use of mRNA vaccines, offer promising alternatives. This review focuses on emerging vaccines GBM treatment. We summarize recent advancements, evaluate current obstacles, discuss notable successes this field. Our analysis highlights that while have shown potential, is still experimental. Ongoing research clinical trials essential fully understand therapeutic potential. Future developments vaccine technology insights into GBM-specific immune responses may lead more targeted effective treatments. Despite promise, further crucial validate optimize effectiveness combating GBM. Graphical

Language: Английский

---

Immune Alterations with Aging: Mechanisms and Intervention Strategies

Nutrients, Journal Year: 2024, Volume and Issue: 16(22), P. 3830 - 3830

Published: Nov. 8, 2024

Aging is the result of a complex interplay physical, environmental, and social factors, leading to an increased prevalence chronic age-related diseases that burden health care systems. As global population ages, it crucial understand aged immune system, which undergoes declines in both innate adaptive immunity. This decline exacerbates aging process, creating feedback loop accelerates onset diseases, including infectious autoimmune disorders, cancer. Intervention strategies, dietary adjustments, pharmacological treatments, immunomodulatory therapies, represent promising approaches counteract immunosenescence. These interventions aim enhance function by improving activity interactions aging-affected cells, or modulating inflammatory responses through suppression excessive cytokine secretion pathway activation. Such strategies have potential restore homeostasis mitigate inflammation, thus reducing risk linked aging. In summary, this review provides insights into effects underlying mechanisms immunosenescence, as well its interventions, with particular emphasis on relationship between aging, immunity, nutritional factors.

Language: Английский

---

Artificially Tagging Tumors with Nano-Aluminum Adjuvant-Tethered Antigen mRNA Recruits and Activates Antigen-Specific Cytotoxic T Cells for Enhanced Cancer Immunotherapy

Biomaterials, Journal Year: 2025, Volume and Issue: 317, P. 123085 - 123085

Published: Jan. 5, 2025

T cell therapy for solid tumors faces significant challenges due to the immune off-target attack caused by loss of tumor surface antigens and inactivation in acidic microenvironment (TME). Herein, we developed a bifunctional immunomodulator (MO@NAL) loading ovalbumin (OVA; model antigen) mRNA (mOVA) onto lysozyme-coated layered double hydroxide nano-aluminum adjuvant (NA). The NA's inherent alkalinity effectively neutralizes excess acid within TME suppresses regulatory cells, creating favorable enhance cytotoxic infiltration activation tumors. Particularly, once internalization MO@NAL efficiently tags with OVA through carried mOVA, providing targets recruiting directing antigen-specific cells destroy cells. In mice pre-vaccinated vaccine, intratumoral administration rapidly awakens OVA-specific memory, inhibiting progression colon melanoma at both early advanced stages. non-pre-vaccinated mice, combining therapeutic vaccine or adoptive transfusion similarly achieves robust suppression. These findings thus underscore potential as an effective safe enhancing responses timely intervention progression.

Language: Английский

---

Construction and Validation of a Novel Butyrylation-Related Gene Signature Related to Prognosis, Clinical Implications, and Immune Microenvironment Characterization of Hepatocellular Carcinoma

ACS Omega, Journal Year: 2025, Volume and Issue: 10(4), P. 3375 - 3388

Published: Jan. 18, 2025

Hepatocellular carcinoma (HCC) is a common and highly lethal malignant tumor that poses serious threat to human health. The post-transcriptional modification of proteins known as butyrylation has emerged critical factor in tumorigenesis, playing pivotal role the initiation progression cancer. This study aimed develop prognostic risk model for HCC using butyrylation-related genes (BRGs). Differentially expressed BRGs were identified from LIHC–TCGA data sets, was constructed LASSO multivariate regression analysis. model's robustness further confirmed GSE14520 cohort. clinicopathological characteristics, immune features, enrichment pathways, antitumor drug sensitivity BRG signature also assessed. Additionally, nomogram created improve predictive accuracy model. A set 16 BRGs, including MMP1, ACOT7, AGPAT5, FLAD1, PDSS1, HSPD1, FKBP1A, AKR1B10, HDAC1, HDAC2, MAPT, ACADS, ACAT1, ACSL6, PDE2A, PON1, identified. Kaplan–Meier survival analysis showed patients high-risk group had worse overall (OS) progression-free (PFS) compared with those low-risk group. Univariate Cox regressions, along analysis, consistently indicated an independent HCC. Clinical line plots accurately predicted 1, 3, 5 year AUC values 0.805, 0.729, 0.710, respectively. distribution cells varied between different groups, more potential immunotherapy chemotherapy. provides novel biological basis prediction offers insights into personalized treatment strategies, candidate selection, clinicians guide therapeutic decisions.

Language: Английский

---

Predictive role of SLC1A5 in neuroblastoma prognosis and immunotherapy

BMC Cancer, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 28, 2025

Neuroblastoma, a prevalent extracranial solid tumor in pediatric patients, demonstrates significant clinical heterogeneity, ranging from spontaneous regression to aggressive metastatic disease. Despite advances treatment, high-risk neuroblastoma remains associated with poor survival. SLC1A5, key glutamine transporter, plays dual role promoting growth and immune modulation. However, its contributions biology remain largely unexplored. This study utilized samples 20 patients 1310 cases four public datasets investigate SLC1A5 expression, biological function, prognostic significance. Differential Kaplan–Meier survival analysis, gene set enrichment weighted correlation network analysis were conducted. Functional validation included qPCR, immunohistochemistry, Western blotting, cell proliferation assays using the inhibitor V-9302. A signature, SRPS, was constructed validated machine-learning approaches. Immune infiltration performed evaluate microenvironment. expression significantly elevated correlated advanced stages prognosis. GSEA revealed mTORC1 signaling high groups, by increased p-p70S6K levels cells. V-9302 treatment suppressed inhibited proliferation. Hub-genes identified form SRPS model, which demonstrated superior performance compared existing models. more immunosuppressive microenvironment expression. Additionally, negatively regulated ST8SIA1, crucial for GD2 biosynthesis, suggesting that inhibition may enhance GD2-directed immunotherapies. pivotal progression shaping an The incorporating SLC1A5-associated genes, offers robust utility. Targeting through drug delivery systems combined metabolic-immunotherapeutic strategies specificity efficacy. These findings provide foundation novel therapeutic approaches improve outcomes patients.

Language: Английский

---

Cancer Cell and Cancer‐Associated Fibroblast Communication‐Mediated Molecular Subtypes Portray Non‐Inflamed Tumor Microenvironment and Guide the Precision Treatment of Bladder Cancer

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

Published: Feb. 17, 2025

Abstract Cancer‐associated fibroblasts (CAFs) drive tumor progression through restructuring of the microenvironment. This investigation aim to elucidate function molecular subtypes (MS) derived from cancer cells communication with CAFs, depicting hallmarks microenvironment and precise bladder (BLCA) treatment. The BLCA data TCGA several external sources are utilized generate a novel ligand, receptor, transcription factor (LRT) associated subtype their corresponding score (LRT score). LRT‐mediated is identified via unsupervised clustering. LRT measured by principal component analysis. Then, association clusters established MS, immunophenotypes, medical endpoints, together treatment strategies investigated. Two (A B) identified. cluster score) can precisely propose classical clinical outcomes, therapeutic strategies. Cluster B (Low represent basal inflamed phenotype specified high immunity against tumors unfavorable outcomes. Furthermore, it highly sensitive immunotherapy; however, has low sensitivity antiangiogenic targeted therapies. strong biological characteristics between cancer‐associated fibroblasts. may be useful clinician tool for developing individualized

Language: Английский

---

Pancreas-targeted lipid nanoparticles for relatively non-invasive interleukin-12 mRNA therapy in orthotopic pancreatic ductal adenocarcinoma

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: 381, P. 113588 - 113588

Published: March 1, 2025

Language: Английский

---