RNA delivery to the corneal endothelium using charge-altering releasable transporters

Exosomes in corneal diseases: advances in diagnosis and therapy

The diagnosis and treatment of corneal diseases still face many challenges. As nanoscale vesicles (30–150 nm in diameter), exosomes facilitate intercellular communication by transporting bioactive molecules such as proteins and nucleic acids. Exhibiting low immunogenicity, minimal toxicity, and engineering versatility, they hold strong promise for both diagnostic and therapeutic applications in corneal diseases. This review provides a comprehensive overview of the current understanding and future directions of exosome research in corneal diseases. We systematically compare traditional and emerging methods for exosome isolation and purification. We then discuss their expanding roles: (1) as diagnostic biomarkers and (2) as therapeutic agents or drug delivery systems, with an emphasis on representative examples and engineering innovations. Finally, we critically assess persistent challenges and outline essential research priorities for clinical translation. Looking forward, we highlight the need for standardized isolation protocols, large-scale production of clinical-grade exosomes, and targeted engineering strategies (e.g., surface modification or cargo loading) to enhance corneal wound healing and immune modulation. The integration of exosome-based therapies with biomaterials and sustained-release platforms may further unlock their potential, paving the way for personalized, off-the-shelf treatments for corneal disorders.

Exosome-based therapies for corneal disorders: current status and future perspectives.

Advances in RNA delivery to extrahepatic tissues and cells.

Despite their transformative potential in treating genetic, neurological, and oncological disorders, the clinical application of RNA therapeutics remains largely confined to the liver. Current approved platforms rely on two fundamentally distinct hepatic delivery mechanisms. N-acetylgalactosamine (GalNAc) conjugation achieves liver targeting through designed, high-affinity binding to the asialoglycoprotein receptor on hepatocytes, while lipid nanoparticles (LNPs) accumulate in the liver through intrinsic physicochemical tropism driven by apolipoprotein adsorption and the fenestrated hepatic vasculature. Extending RNA delivery beyond the liver demands solutions to challenges that have no hepatic parallel, including formidable tissue-specific physiological barriers, critically low endosomal escape efficiencies, and the absence of any extrahepatic receptor-ligand system matching the efficiency and recyclability of the GalNAc-ASGPR axis. In this review, we critically examine recent progress in engineering delivery systems to access representative extrahepatic tissues, including the central nervous system(CNS), eye, lung, heart, spleen, inner ear, and bone marrow. We evaluate the rational design of viral vectors, polymeric and lipid-based nanocarriers, exosome platforms, hydrogel depot systems, and local administration strategies that bypass systemic clearance. By analyzing the molecular mechanisms, translational milestones, and persisting limitations of these approaches, this review identifies the key scientific and engineering bottlenecks that must be resolved to advance extrahepatic RNA therapeutics from preclinical promise toward broad clinical reality.

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.

Efficient genome editing in the non-human primate brain using programmable extracellular vesicles

Encapsulated cell technology delivers ciliary neurotrophic factor to promote JAK/STAT-dependent photoreceptor survival in retinal degeneration

Sustained trophic factor delivery via Encapsulated Cell Technology (ECT) is a powerful new class of therapeutics with broad potential for targeted treatment. Intravitreal delivery of ciliary neurotrophic factor (CNTF) via the ECT, NT-501, is a first-in-class therapy that slows the progression of macular telangiectasia type 2 (MacTel). Despite its clinical efficacy, key questions remain regarding its mechanism of action, including whether other implant-derived factors contribute to therapeutic benefit and how optimal dosing should be determined. Resolving these issues is critical for optimizing NT-501 in MacTel and guiding the development of ECT-based therapies for other diseases. We evaluated the biological activity of implant-derived cytokines on retinal tissue, using long-term NT-501 intravitreal implants in rabbits alongside human retinal organoid (hRO) models treated with NT-501–conditioned medium (NT-501–CM). Then, using a MacTel-specific photoreceptor degeneration model in hROs, we showed NT-501–CM significantly reduced photoreceptor cell death, and this protective effect was abolished by either CNTF-neutralizing antibodies or JAK inhibitor. We also established a therapeutic dose-response relationship linking NT-501–derived CNTF levels to JAK/STAT3 activation and photoreceptor protection. These findings directly connect ECT-derived CNTF exposure with JAK/STAT3-mediated photoreceptor protection in human retinal tissue and suggest an optimal concentration range for efficacy.