Host Immune Responses to Viral and Non-Viral Gene Therapy: Mechanisms, Modulation, and the Path to Durable Treatment

The field of gene and cell therapy has entered a transformative phase, with viral and non‑viral delivery systems enabling precise correction of genetic defects and unprecedented therapeutic potential in complex diseases. Yet immune recognition remains a pivotal challenge across these modalities. Both innate and adaptive responses can compromise safety, limit transgene durability, prevent redosing, and trigger systemic inflammation. While advances in adeno‑associated virus (AAV), lipid nanoparticles (LNPs), and DNA- or RNA-based approaches have expanded the therapeutic landscape, understanding and controlling host immunogenicity has become central to the viability and scalability of genetic medicines. Current research seeks to disentangle vector‑specific immune pathways, identify determinants of immunotoxicity, and integrate immunosuppressive and immunomodulatory strategies capable of modulating host immunity and sustaining long‑term efficacy. Despite active progress, important knowledge gaps persist in elucidating immune tolerance induction, standardizing predictive assays, and translating preclinical findings into human systems.This Research Topic aims to explore the mechanisms and modulation of immune responses elicited by both viral and non‑viral gene therapies. It encourages studies that dissect innate pattern‑recognition activation, adaptive antibody and T‑cell responses against vectors or transgene products, and innovations that mitigate these reactions. Authors are invited to address how immunology interfaces with gene delivery platform design, manufacturing processes, and clinical outcomes, contributing to a comprehensive understanding that supports safe, repeatable, and durable treatment. Experimental, computational, and clinical approaches that integrate immunological profiling with therapeutic development are particularly welcome.To gather further insights within the boundaries of translational gene medicine, we welcome contributions addressing, but not limited to, the following themes:- Immunogenicity and tolerance mechanisms in viral and non‑viral delivery platforms- Innate sensing, complement activation, thrombocytopenia, endothelial damage, and inflammatory signaling in gene transfer- Pre‑existing immunity and its impact on dosing strategy and patient selection- Immunosuppressive and Immunomodulatory interventions including corticosteroids, calcineurin and mTOR inhibitors, anti-metabolites, biologics, and engineered tolerance systems- Non-enzymatic, enzymatic and extra-corporeal antibody depletion strategies to enable dosing of seropositive patients including small molecules, IdeS and IdeS-like enzymes, biologics, plasmapheresis, and affinity columns.- Next‑generation assay technologies for assessing vector and transgene immune responses- Durability of transgene expression, long‑term immune surveillance, and re‑administration feasibility- Nano‑ and micro‑particle delivery interfaces: protein corona formation, vesicle biology, and immunological effects- Deimmunization strategies including vector and transgene modifications- Translational and regulatory considerations shaping immune safety evaluation in clinical gene therapy Topic editors: Sury Somanathan, Moanaro Biswas, Sandeep Kumar Source: https://www.frontiersin.org/research-topics/83029/host-immune-responses-to-viral-and-non-viral-gene-therapy-mechanisms-modulation-and-the-path-to-durable-treatment