Jul 2026· International Journal of Drug Delivery Technology· 0 citations· 47 references
Abstract
Background
CRISPR-Cas genome editing offers curative potential for monogenic disorders and persistent infections, but its
clinical translation is hindered by delivery inefficiency, off-target effects, and immunogenicity. Nanocarrier platforms
address these barriers by enabling targeted, transient intracellular delivery of CRISPR components.
Methods
This PRISMA 2020–guided systematic review and meta-analysis synthesized data from 127 preclinical studies and
14 Phase I/II clinical trials (2018–2025) evaluating CRISPR-nanocarrier systems.
Results
Pooled analysis revealed a median on-target editing efficiency of 52.4% (95% CI: 48.1–56.7). Ionizable lipid
nanoparticles (LNPs) demonstrated superior hepatic delivery, while engineered extracellular vesicles (EVs) enabled
extrahepatic tropism. Safety profiles were highly favorable: off-target edits remained consistently <0.1%,
chromosomal aberrations were negligible (98.4% compliance), and pathogen loads decreased by 3.12 log₁₀. Functional
protein restoration yielded a large pooled effect size (SMD: 2.84). Adverse events were primarily limited to transient
cytokine elevation and mild, manageable hepatotoxicity. Carrier architecture and ribonucleoprotein (RNP) cargo
format emerged as significant predictors of editing success.
Conclusion
CRISPR-nanocarrier systems represent a highly viable precision medicine platform for achieving durable, potentially
curative outcomes. Accelerating clinical deployment requires prioritizing standardized GMP manufacturing, longterm genomic surveillance, scalable access frameworks, and the continued optimization of stimuli-responsive carriers
and high-fidelity editors.
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
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
The clinical translation of CRISPR- Cas9 therapeutics requires rigorous and biologically grounded evaluation of genome editing fidelity that extends beyond conventional measures of on-target efficiency and canonical off-target detection. Existing fidelity assessment strategies often capture limited aspects of editing outcomes and do not fully account for context-dependent biochemical, epigenetic, and cellular heterogeneity that can influence therapeutic safety and efficacy. This review focuses on analytical and translational frameworks for CRISPR fidelity assessment, with emphasis on the strengths and limitations of current bioanalytical platforms. Recent advances integrating orthogonal technologies including digital droplet PCR, genome-wide off-target mapping approaches (e.g., CIRCLE-seq and GUIDE-seq), and single-cell proteogenomic profiling enable more comprehensive characterization of editing outcomes across molecular and functional dimensions. Applications in edited T cells targeting immune checkpoints and in hematopoietic stem cell correction models illustrate how multi-layered analyses can reveal context-dependent variability and previously undetected off-target effects. Emerging approaches, including integrative scoring frameworks and AI-assisted analytical models, are discussed in an exploratory context, with emphasis on current limitations, validation requirements, and challenges in standardization. In addition, ongoing efforts toward minimally invasive monitoring strategies are considered with respect to their potential, as well as their current constraints. Despite significant progress, major challenges remain in assay harmonization, cross-platform comparability, and translation to clinically actionable frameworks. Accordingly, CRISPR fidelity is best understood as a multi-dimensional biological phenotype that requires careful, context-specific evaluation. This perspective provides a balanced foundation for advancing genome editing toward safer and more reliable therapeutic applications.
Arpita Mukherjee· Journal of Rare Diseases· 1 citation
The advent of CRISPR/Cas9 genome editing has significantly transformed the landscape of cancer therapeutics by facilitating precise and programmable manipulation of disease-associated genetic modifications. This review comprehensively evaluates the current clinical and translational landscape of CRISPR/Cas9-based cancer therapies through an analysis of published literature and registered clinical trials. The current CRISPR/Cas9 applications in oncology are primarily centred on three mechanistic strategies: immune cell engineering for enhanced tumor recognition, direct targeting of oncogenic mutations, and modulation of tumor-supportive pathways. Analysis of 32 clinical trials indicates that CRISPR-based interventions have demonstrated encouraging safety profiles and early signs of clinical activity, particularly in ex vivo engineered immune-cell therapies. Notable examples include CRISPR-edited CAR-T cell products targeting CD19 and BCMA, which have achieved objective responses in relapsed or refractory hematological malignancies while demonstrating sustained persistence of edited cells in vivo. In contrast, clinical translation into solid tumors remains comparatively limited due to challenges associated with delivery efficiency, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Technological advancements, including multiplex genome editing, base editing, and prime editing have expanded the precision and versatility of CRISPR-based interventions, while integration with immunotherapy and nanotechnology-based delivery systems continues to broaden therapeutic potential. Despite these advances, several significant challenges still need to be addressed, including off-target editing, manufacturing scalability, delivery limitations, and regulatory considerations. Overall, CRISPR/Cas9 represents a promising yet evolving platform in oncology, with its future clinical success dependent on achieving a balance between precision, safety, scalability, and long-term therapeutic durability.
Chu Xin Ng, Sakina Mustafa, X. Y. Yap et al.· Frontiers in Oncology· 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
CRISPR-based genome editing has transformed the therapeutic possibilities of genomic medicine by enabling programmable modification of disease-associated genes and regulatory pathways. This review analyzed the evolution, current clinical applications, emerging therapeutic strategies, safety limitations, ethical challenges, and future perspectives of CRISPR-based technologies within an international framework that incorporates Latin America. An integrative literature review was conducted using scientific evidence published between 2012 and July 2026, with emphasis on peer-reviewed studies indexed in major biomedical databases and relevant international and regulatory documents. The evidence showed a rapid progression from foundational CRISPR-Cas9 research toward base editing, prime editing, ex vivo cellular modification, and direct in vivo genome editing. Clinical translation was most advanced in hematology, particularly in sickle cell disease and transfusion-dependent β-thalassemia, where genome-edited autologous hematopoietic stem and progenitor cells have demonstrated clinically meaningful therapeutic outcomes. Applications in oncology and hereditary transthyretin amyloidosis further demonstrated the feasibility of engineered immune cells and systemic in vivo genome editing. However, broader clinical implementation remains limited by delivery and tissue targeting, off-target and unintended on-target modifications, immunogenicity, manufacturing complexity, long-term safety, regulatory requirements, and accessibility. The international analysis identified heterogeneous capacity for clinical implementation, emphasizing the need to strengthen genomic infrastructure, population representation, professional training, regulatory preparedness, and research participation in Latin America. CRISPR has therefore progressed from an experimental genome-engineering technology to a clinically relevant therapeutic platform, although its future impact will depend on the ability to combine molecular precision and durable therapeutic benefit with rigorous safety assessment, responsible governance, and equitable access across diverse populations and healthcare systems.
Gabriel Alejandro, Ortega Moreno, G. Amaya et al.· International science journa...· 0 citations