Rational design of ICD-inducing nanoparticles for cancer immunotherapy

Science Advances, Journal Year: 2024, Volume and Issue: 10(6)

Published: Feb. 7, 2024

Nanoparticle-based cancer immunotherapy has shown promising therapeutic potential in clinical settings. However, current research mainly uses nanoparticles as delivery vehicles but overlooks their to directly modulate immune responses. Inspired by the endogenous endoplasmic reticulum (ER) stress caused unfolded/misfolded proteins, we present a rationally designed immunogenic cell death (ICD) inducer named NanoICD, which is nanoparticle engineered for ER targeting and retention. By carefully controlling surface composition properties, have obtained NanoICD that can effectively accumulate ER, induce stress, activate ICD-associated In addition, generally applicable various proteins enzymes further enhance immunomodulatory capacity, exemplified encapsulating catalase (CAT) obtain NanoICD/CAT, alleviated immunosuppressive tumor microenvironment induced robust antitumor responses 4T1-bearing mice. This work demonstrates nanostructures' autonomously regulate biological processes provides insights into development of advanced nanomedicines treatment.

Language: Английский

---

Cancer Nanovaccines: Nanomaterials and Clinical Perspectives

Small, Journal Year: 2024, Volume and Issue: 20(35)

Published: May 1, 2024

Abstract Cancer nanovaccines represent a promising frontier in cancer immunotherapy, utilizing nanotechnology to augment traditional vaccine efficacy. This review comprehensively examines the current state‐of‐the‐art nanovaccine development, elucidating innovative strategies and technologies employed their design. It explores both preclinical clinical advancements, emphasizing key studies demonstrating potential elicit robust anti‐tumor immune responses. The study encompasses various facets, including integrating biomaterial‐based nanocarriers for antigen delivery, adjuvant selection, impact of nanoscale properties on performance. Detailed insights into complex interplay between tumor microenvironment responses are provided, highlighting challenges opportunities optimizing therapeutic outcomes. Additionally, presents thorough analysis ongoing trials, presenting snapshot landscape. By curating latest scientific findings developments, this aims serve as comprehensive resource researchers clinicians engaged advancing immunotherapy. Integrating design holds immense promise revolutionizing treatment paradigms, provides timely update evolving landscape nanovaccines.

Language: Английский

---

Recent Advances in Lipid Nanoparticles and Their Safety Concerns for mRNA Delivery

Vaccines, Journal Year: 2024, Volume and Issue: 12(10), P. 1148 - 1148

Published: Oct. 8, 2024

The advent of lipid nanoparticles (LNPs) as a delivery platform for mRNA therapeutics has revolutionized the biomedical field, particularly in treating infectious diseases, cancer, genetic disorders, and metabolic diseases. Recent Advances Therapeutic LNPs: LNPs, composed ionizable lipids, phospholipids, cholesterol, polyethylene glycol (PEG) facilitate efficient cellular uptake cytosolic release while mitigating degradation by nucleases. However, synthetic entities, LNPs face challenges that alter their therapeutic efficacy safety concerns. Toxicity/Reactogenicity/Immunogenicity: This review provides comprehensive overview latest advancements LNP research, focusing on preclinical assessments encompassing toxicity, reactogenicity, immunogenicity. Summary Outlook: Additionally, it outlines potential strategies addressing these offers insights into future research directions enhancing application therapeutics.

Language: Английский

---

Engineering LNPs with polysarcosine lipids for mRNA delivery

Bioactive Materials, Journal Year: 2024, Volume and Issue: 37, P. 86 - 93

Published: March 16, 2024

Since the approval of lipid nanoparticles (LNP)-mRNA vaccines against SARS-CoV-2 virus, there has been an increased interest in delivery mRNA through LNPs. However, current LNP formulations contain PEG lipids, which can stimulate generation anti-PEG antibodies. The presence these antibodies potentially cause adverse reactions and reduce therapeutic efficacy after administration. Given widespread deployment COVID-19 vaccines, exposure to may necessitate evaluation alternative without components. In this study, we investigated a series polysarcosine (pSar) lipids as alternatives determine whether pSar could still provide functionality ALC-0315 SM-102 systems. We found that complete replacement with increase or maintain efficiency exhibit similar safety profiles vivo.

Language: Английский

---

Optimized inhaled LNP formulation for enhanced treatment of idiopathic pulmonary fibrosis via mRNA-mediated antibody therapy

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 9, 2024

Lipid nanoparticle-assisted mRNA inhalation therapy necessitates addressing challenges such as resistance to shear force damage, mucus penetration, cellular internalization, rapid lysosomal escape, and target protein expression. Here, we introduce the innovative "LOOP" platform with a four-step workflow develop inhaled lipid nanoparticles specifically for pulmonary delivery. iLNP-HP08LOOP featuring high helper ratio, acidic dialysis buffer, excipient-assisted nebulization demonstrates exceptional stability enhanced expression in lungs. By incorporating encoding IL-11 single chain fragment variable (scFv), scFv@iLNP-HP08LOOP effectively delivers secretes scFv lungs of male mice, significantly inhibiting fibrosis. This formulation surpasses both intravenously injected fibroblast activation extracellular matrix deposition. The HP08LOOP system is also compatible commercially available ALC0315 LNPs. Thus, method presents powerful developing nanotherapeutics potential treating various respiratory diseases, including idiopathic Inhaled face several when delivered authors show "LOOP"-optimized could withstand damage generated during process be used mRNA-mediated antibody

Language: Английский

---

Ionizable Lipids with Optimized Linkers Enable Lung-Specific, Lipid Nanoparticle-Mediated mRNA Delivery for Treatment of Metastatic Lung Tumors

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

Published: Feb. 6, 2025

Lipid nanoparticles (LNPs) have emerged as a groundbreaking delivery system for vaccines and therapeutic mRNAs. Ionizable lipids are the most pivotal component of LNPs due to their ability electrostatically interact with mRNA, allowing its encapsulation while concurrently enabling endosomal escape following cellular internalization. Thus, extensive research has been performed optimize ionizable lipid structure develop formulations that well tolerated allow efficient targeting different organs result in high sustained mRNA expression. However, one facet lipids' mostly overlooked: linker segment between headgroup tails. Here, we screened rationally designed library biodegradable linkers. We extensively characterized formulated using these elucidated how minor structural changes radically influenced LNPs' biodistribution vivo. showed use amide urea linkers can modulate pKa, resulting an improved specificity lung transfection. Finally, demonstrated (lipid 35) form entrapping bacterial toxin [pseudomonas exotoxin A (mmPE)] reduced tumor burden significantly increased survival mice metastasis.

Language: Английский

---

Why Do Lipid Nanoparticles Target the Liver? Understanding of Biodistribution and Liver-Specific Tropism

Molecular Therapy — Methods & Clinical Development, Journal Year: 2025, Volume and Issue: 33(1), P. 101436 - 101436

Published: Feb. 16, 2025

Lipid nanoparticles (LNPs) are now highly effective transporters of nucleic acids to the liver. This liver-specificity is largely due their association with certain serum proteins, most notably apolipoprotein E (ApoE), which directs them liver cells by binding low-density lipoprotein (LDL) receptors on hepatocytes. The liver's distinct anatomy, its various specialized cell types, also influences how LNPs taken up from circulation, cleared, and they in delivering treatments. In this review, we consider factors that facilitate LNP's targeting explore latest advances liver-targeted LNP technologies. Understanding targeted can help for design optimization nanoparticle-based therapies. Comprehension cellular interaction biodistribution not only leads better treatments diseases but delivers insight directing other tissues, potentially broadening range therapeutic applications.

Language: Английский

---

Extracellular vesicle-mediated VEGF-A mRNA delivery rescues ischaemic injury with low immunogenicity

European Heart Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

Abstract Background and Aims Lackluster results from recently completed gene therapy clinical trials of VEGF-A delivered by viral vectors have heightened the need to develop alternative delivery strategies. This study aims demonstrate pre-clinical efficacy safety extracellular vesicles (EVs) loaded with mRNA for treatment ischaemic vascular disease. Methods After encapsulation full-length into fibroblast-derived EVs via cellular nanoporation (CNP), collected were mouse models injury. Target tissue was verified in situ analysis protein expression. Functional rescue confirmed vivo imaging histology. The single serial demonstrated using immune-based assays. Results generated high content a CNP methodology. EV administration expression exogenous RNA hybridization elevated western blot, microscopy, enzyme-linked immunosorbent assay. Mice treated human after femoral or coronary artery ligation exhibited neovascularization tissues increased arterial perfusion improvement left ventricular function, respectively. Serial VEGF-EVs injured skin showed improved wound healing repeat administration. Importantly, as compared adeno-associated lipid nanoparticle modalities, murine did not trigger innate adaptive immune responses at injection site systemically. Conclusions that offers efficient, dose-dependent formation low immunogenicity, resulting new vessel

Language: Английский

---

Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 3, 2025

Language: Английский

---

Identification of Cell Receptors Responsible for Recognition and Binding of Lipid Nanoparticles

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7604 - 7616

Published: Feb. 24, 2025

Effective delivery of lipid nanoparticles (LNPs) and their organ- or cell-type targeting are paramount for therapeutic success. Achieving this requires a comprehensive understanding protein corona dynamics the identification cell receptors involved in recognition uptake LNPs. We introduce simple, fast, situ strategy by biosensor-based "Fishing" method to uncover formation on LNPs identify key human blood cells that responsible binding plasma surface Unexpectedly, we observed significant presence immunoglobulins with high abundance, especially anti-PEG antibodies, within LNP corona. These along complement opsonization, drive colony-stimulating factor 2 receptor β (CSF2RB)-mediated phagocytosis myeloid cells. compositions interactions neighboring proteins critical cellular uptake. Our findings highlight pivotal role antibodies circulation vivo. This approach offers profound insights into nanomaterial behavior vivo, paving way enhanced design efficacy LNP-based therapies.

Language: Английский

---