Jul 2026· Journal of Controlled Release· pp.
115204
· 0 citations· 200 references
Medicine
TL;DR
This review examines how biophysical properties of viral vectors, lipid nanoparticles, and hybrid virus-like particles influence editor delivery performance and explores how the notion of carrier systems shifts in diseased states like solid tumour cancers, autoimmune psoriasis of the skin, and the autosomal monogenic cystic fibrosis.
Abstract
CRISPR-based genome editing has opened new pathways towards precision medicine, but its success depends on more than just molecular engineering. Cargo and carrier dynamics are profoundly influenced by the underlying biophysical properties of cells and vectors. Consequently, this domain is moving beyond simple "lock and key" approaches, and towards disease-customised fits. In this review, we examine how biophysical properties of viral vectors, lipid nanoparticles, and hybrid virus-like particles influence editor delivery performance. We examine parameters such as size, cargo capacity, charge, shape, stiffness, membrane composition, internalisation strategies, tropism, endosomal escape, protein corona formation, and immune recognition as key drivers of intelligent, modular engineering. Finally, we explore how the notion of carrier systems shifts in diseased states like solid tumour cancers, autoimmune psoriasis of the skin, and the autosomal monogenic cystic fibrosis, where altered biophysical landscapes demand adaptable, context-informed genome editing solutions.
This article aims to provide a working framework for verifying the potency, genomic integrity, and clinical safety of vector-based gene therapies—one intended to be useful both to laboratories developing these products and to those responsible for regulating them.
Yusra A. Radeef, Z. Abdullah, Eman Fadhel Abbas Awadh· International Journal of Mul...· 0 citations
Therapeutic genome editing has advanced rapidly with the development of diverse programmable nucleases, from zinc‐finger nucleases and transcription activator‐like effector nucleases to clustered regularly interspaced short palindromic repeats (CRISPR)‐based systems such as base and prime editors. Despite these breakthroughs, clinical translation remains constrained by the challenge of achieving safe, efficient, and tissue‐specific delivery. Viral vectors, particularly adeno‐associated viruses, have enabled durable editing in selected organs but are limited by their restricted cargo capacity, immunogenicity, and complex manufacturing. Nonviral platforms, most notably ionizable lipid nanoparticles, have demonstrated remarkable efficacy for hepatic targets, with clinical trials reporting up to 93% protein knockdown after a single dose. An expanding set of emerging modalities, including virus‐mimicking nanosystems, cell‐derived extracellular vesicles, cell‐penetrating peptides, and intelligent‐responsive multifunctional scaffolds, further enriches the delivery toolbox by supporting transient expression and programmable targeting across diverse editors and tissues. Parallel advances in high‐throughput barcoded screening and machine learning are accelerating vector optimization, while rational chemical modification of payloads improves in vivo stability and specificity. This review provides a comprehensive overview of current and emerging delivery systems for genome editing, highlighting key innovations, unresolved challenges, and interdisciplinary strategies poised to unlock broader therapeutic potential.
Meijia Yang, Yiqiong Song, Ziyang Wang et al.· MedComm· 0 citations
CRISPR/Cas9 has revolutionized genetic engineering since its repurposing as a programmable nuclease in 2012, yet its clinical translation remains fundamentally constrained by delivery barriers rather than editing efficiency. The system operates through acquisition, biogenesis, and interference mechanisms, but therapeutic application necessitates overcoming delivery challenges that are highly context-dependent. This review moves beyond a descriptive summary of 67 studies to provide a critical, barrier-focused analysis of delivery strategies. Our re-analysis of the tabulated data identifies quantitative trends across viral, non-viral, and physical platforms, evaluates trade-offs between efficiency and safety, and proposes a decision framework for vehicle selection based on target tissue and cargo type. A major focus of this review is the inclusion of recent hybrid systems (VLPs, SORT-LNPs) and the recognition that chemical modification of guide RNAs is a critical parameter for therapeutic success. A key forward-looking insight is that hybrid systems and stimuli-responsive nanoparticles are poised to dominate the next 5 years of clinical development, particularly for liver, CNS, and hematopoietic targets. Successful clinical translation of CRISPR/Cas9 will depend on context-specific delivery strategies that balance editing efficiency, safety, and clinical scalability.
M. Rezaee, F. Izadi, Saeed Nobaharian et al.· Beni-Suef University Journal...· 0 citations
Content of image described in text. Abstract Background Gene therapy has emerged as a transformative approach for treating diseases that are caused by genetic defects, including cancer, inherited metabolic disorders and immunodeficiencies. However, its clinical success depends critically on the availability of safe, efficient and non-immunogenic delivery systems. Conventional viral vectors, while highly effective, are associated with immunogenicity, oncogenic risk and high production costs. Non-viral alternatives offer improved safety but they have lower transfection efficiency and limited stability. Exosomes are naturally secreted, endosome-derived nanovesicles ranging from 30–150 nm in diameter and have emerged as promising next-generation carriers for gene and drug delivery. Their inherent biocompatibility, low immunogenicity, ability to cross biological barriers and capacity to transport diverse molecular cargo including nucleic acids, proteins and small molecules make them particularly attractive as therapeutic platforms. Methods This review summarizes the biogenesis, molecular composition and classification of exosomes and examines their applications in siRNA/miRNA delivery, CRISPR/Cas9 gene editing, mRNA therapy, cancer treatment and vaccine development. Special attention is given to engineered, plant-derived and stem cell-derived exosomes, as well as current cargo-loading strategies and commercial therapeutic platforms. Results Despite their promise, significant challenges remain, including low cargo-loading efficiency, batch heterogeneity, limited scalability and the absence of standardized manufacturing and regulatory frameworks. Conclusions Future research must address these barriers to accelerate the clinical translation of exosome-based therapeutics.
Elza Karabagh, Babek Alibayov, Adil Allahverdiyev· Expert Reviews in Molecular...· 0 citations
Nanotechnology has become an important platform in the fields of gene therapy and genome editing, providing delivery strategies that address persistent therapeutic challenges by improving the precision, efficiency, and safety of genetic modifications. This review highlights the central role of nanomaterials in overcoming persistent barriers to genetic interventions, including inefficient delivery, instability of genetic cargo, and off-target effects. Specifically, we emphasize the combined use of nanomaterials with clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR-Cas) systems, which can improve editing specificity and therapeutic efficacy. Beyond the classical CRISPR/Cas9 platform, this review also discusses next-generation modalities such as base editors, Cas13, prime editing, and the recently described Tandem Interspaced Guide RNA and TIGR-associated protein (TIGR-Tas) system, while considering their therapeutic potential and distinct delivery challenges. By using nanomaterials, the stability and intracellular delivery of genome-editing systems are improved, enabling more effective treatments for genetic disorders and acquired diseases such as cancer and infectious diseases. In addition, nanocarriers provide controlled release, protection from degradation, and better biocompatibility, thereby improving the safety and reliability of gene-editing therapies. Despite these advances, important translational challenges remain, including immunotoxicity, large-scale manufacturing, and regulatory integration. Overall, the continued convergence of nanotechnology and genome engineering may support the development of personalized medicine strategies that adapt genetic engineering tools for patient-specific applications.
Raheem Mais, Ayush Kumar, Armand Ahmetaj et al.· International Journal of Mol...· 0 citations
The CRISPR-Cas9 genome-editing system has emerged as a promising technology for the precise correction of disease-causing mutations and has shown significant potential in treating various genetic disorders. However, the successful clinical application of CRISPR-Cas9 largely depends on the development of safe and efficient delivery systems. Among the available approaches, nanoparticle-mediated delivery has gained considerable attention for its low immunogenicity, high biocompatibility, improved targeting, and capacity to deliver diverse CRISPR cargoes. This review summarises the current strategies of nanoparticle-mediated CRISPR-Cas9 delivery, including lipid, polymeric, hybrid, inorganic, and biomimetic nanoparticles. It also discusses major pharmacological challenges such as off-target effects, biodistribution, endosomal escape, immunogenicity, toxicity, and regulatory considerations. Furthermore, recent therapeutic applications in genetic disorders, including sickle cell disease, β-thalassemia, Duchenne muscular dystrophy, cystic fibrosis, hereditary transthyretin amyloidosis, and cancer, are highlighted. Finally, future perspectives on advanced nanocarrier design and clinical translation are discussed. Nanoparticle-mediated CRISPR-Cas9 delivery holds great promise for advancing precision medicine and developing effective therapies for genetic disorders.
Shouvik Mondal, Kriti Kumari· Advanced International Journ...· 0 citations