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Results for “Endosomal escape”

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6 recordsLinked to original sources

PubMed2026

Nitric oxide-assisted lipid nanoparticles amplify mRNA vaccine responses.

mRNA vaccines have made substantial clinical advances, yet their full clinical potential can be further expanded by enhancing cytosolic delivery. Here, we integrate a nitric oxide (NO) generator with lipid nanoparticles (LNPs) to boost mRNA delivery efficiency and mRNA-based vaccine efficacy. SM-102/DEA LNPs, the lead formulation, achieved significantly higher mRNA delivery compared with the FDA approved SM-102 LNPs in both cellular and animal models. The intramuscular administration of SM-102/DEA LNPs encapsulating mRNA encoding SARS-CoV-2 spike protein elicited substantially higher anti-spike IgG levels and robust CD8+ and CD4+ T cell responses compared to SM-102 LNPs. Mechanistic studies revealed that DEA incorporation promotes endosomal escape of mRNA cargos in SM-102/DEA LNPs. These findings establish NO-assisted LNPs as a unique platform for potent mRNA delivery, which provides a new paradigm for overcoming endosomal barriers and improving the efficacy of mRNA vaccines.

COVID-19↗

PubMed2026

Targeted Nanoparticle Delivery CRISPR/Cas9: overcoming biological barriers, enhancing stability, and improving therapeutic precision.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has emerged as a promising gene-editing platform for genetic disorders; however, its in vivo application remains limited by low delivery efficiency and biological barriers. Many CRISPR payloads fail to reach target sites due to extracellular degradation, immune clearance, and intracellular trafficking limitations. This review examines the interplay between biological barriers and nanoparticle engineering strategies for CRISPR/Cas9 delivery. A barrier-oriented engineering approach is proposed as a central framework, encompassing ligand-based surface modification for enhanced targeting and uptake, improved circulation stability via PEGylation and biomimetic coatings, and optimized payload release through endosomal escape strategies. Stimulus-responsive nanoparticle systems further enable spatiotemporal control over payload release. Nuclear targeting strategies, including optimization of nuclear localization signals (NLS) and exploitation of endogenous trafficking pathways, are highlighted as key factors for improving genome-level editing efficiency. Despite these advances, major challenges-including limited intracellular delivery efficiency, insufficient targeting precision, and safety concerns-continue to hinder clinical translation. Future directions highlight artificial intelligence-driven nanoparticle design, personalized delivery systems, and next-generation CRISPR platforms. Overall, an integrated, barrier-oriented engineering strategy is essential for advancing CRISPR/Cas9 delivery toward clinical applications, ultimately advancing global good health and well-being.

CRISPR/Cas9↗

PubMed2026

Engineering CRISPR nanoplatforms to deplete cancer stem cells: Delivery checkpoints, target plasticity, and clinical viability.

Cancer stem cells (CSCs) sustain tumor initiation, therapy resistance, and relapse, yet evade durable control because they switch phenotype, enter quiescence, shelter within protective niches, resist drug efflux, and share markers with normal stem cells. Programmable CRISPR editing can disable intracellular self-renewal dependencies that antibodies and small molecules cannot reach, whereas only nanoscale carriers can confine such editing to intended cells; neither component alone solves the CSC problem. This review reframes CSC-directed CRISPR nanomedicine as an integrated design problem. We examine why target plasticity defeats static single-marker targeting; the sequential delivery checkpoints spanning blood stability, organ selection, tumor penetration, CSC recognition, endosomal escape, and productive editing; and advanced architectures including organ-selective lipid nanoparticles, biomimetic and vesicle carriers, metal-organic frameworks, and logic-gated systems. Genotoxicity, immunogenicity, incomplete depletion, manufacturing reproducibility, and absent CSC-specific clinical evidence remain limiting. Clinical viability, not imminent cure, is the realistic near-term objective.

Neoplastic Stem Cells↗

PubMed2026

Engineering extracellular vesicles for targeted siRNA delivery: Advances, therapeutic applications, and clinical translation.

Small interfering RNA (siRNA) therapeutics have emerged as a transformative approach for sequence-specific gene silencing, offering the potential to treat a broad spectrum of diseases by selectively suppressing disease-associated genes. However, the clinical translation of siRNA remains limited by rapid enzymatic degradation, poor cellular uptake, inadequate endosomal escape, and off-target effects, necessitating the development of efficient delivery systems. Extracellular vesicles (EVs) have gained considerable attention as natural nanocarriers owing to their excellent biocompatibility, low immunogenicity, intrinsic targeting capability, and ability to protect therapeutic cargo while traversing complex biological barriers. This review comprehensively discusses the biological characteristics of EVs, the molecular basis of RNA interference, and the major challenges associated with siRNA delivery [Fig. 1]. Recent advances in EV engineering, including cargo-loading strategies such as electroporation, sonication, extrusion, parent-cell engineering, and microfluidic approaches, together with surface functionalization using peptides, antibodies, aptamers, and hybrid nanoplatforms, are critically evaluated for improving targeting specificity and intracellular delivery. Furthermore, the therapeutic applications of engineered EV-mediated siRNA delivery in cancer, neurological disorders, liver diseases, cardiovascular diseases, inflammatory disorders, and infectious diseases are systematically summarized, highlighting their potential to enhance gene silencing while minimizing systemic toxicity. Current challenges related to large-scale manufacturing, cargo-loading efficiency, standardization, quality control, regulatory approval, and clinical translation are also discussed, together with emerging technologies involving synthetic biology, genome engineering, artificial intelligence, and multifunctional hybrid vesicles. Overall, engineered extracellular vesicles represent a highly versatile and biologically inspired platform for targeted siRNA delivery, providing a promising foundation for the development of next-generation precision RNA therapeutics and accelerating the clinical translation of gene-silencing strategies.

Extracellular vesicle engineering↗

PubMed2026

The present and future of nonviral delivery-based genome editing for hereditary hearing loss.

PURPOSE OF REVIEW: This review summarizes nonviral genome-editing delivery platforms for hereditary hearing loss, focusing on lipid nanoparticles (LNPs) and engineered virus-like particles (eVLPs), and discusses their advantages over adeno-associated virus-based delivery, as well as the barriers to clinical translation. RECENT FINDINGS: Recent advances have established LNPs as a clinically advanced nonviral platform, although challenges related to inner ear biodistribution, cell type specificity, endosomal escape, and immunogenicity remain to be addressed. In parallel, eVLPs have undergone substantial technical evolution, progressing from early low efficiency systems to advanced base editor- and prime editor-eVLP architectures that enhance cargo loading and editing efficiency. Extracellular vesicle-based genome editing has also emerged as an additional platform, although issues related to reproducibility, loading efficiency, and scalability remain major hurdles. SUMMARY: Nonviral genome editing platforms expand the therapeutic toolkit for hereditary hearing loss by enabling transient delivery of genome editors with potential safety advantages. Future efforts should focus on characterizing biodistribution and immunogenicity, refining cell type-specific tropism, and establishing scalable manufacturing processes to enable successful clinical translation.

Humans↗

PubMed2026

Redox-activated cholesterol-dependent cytolysin enables cytosolic release of liposomal cargo.

Precise intracellular delivery of biologic therapeutics remains a major challenge due to endosomal entrapment and inefficient delivery systems. Here, we develop a bioinspired platform that uses Streptolysin O (SLO), a member of the cholesterol-dependent cytolysin (CDC) family, for cytosolic cargo delivery. This delivery system incorporates an affibody for selective targeting and endocytosis and a redox-cleavable PEG-conjugated dithiol-ethyl carbonate linker (PEG-DEC) that reversibly inactivates SLO extracellularly. After endosomal uptake, the reductive intracellular environment removes the PEG layer, reactivating SLO to induce localized endosomal disruption and cargo release. This mechanism minimizes off-target toxicity while promoting efficient cytosolic delivery of diverse cargo, including doxorubicin (DOX), the fluorescent protein GFP and mApple, and the enzyme NanoLuciferase (NanoLuc) and lactate oxidase (LOX). PEGylated SLO exhibited significantly improved cytosolic release efficiency compared with conventional liposomal formulations, confirming the advantage as a controllable intracellular delivery module.

Liposomes↗