Purpose of review: To date, various genes associated with inherited disorders and other non-genetic diseases have been revealed with the aid of cutting-edge genomics technologies, suggesting the tremendous potential of gene therapy in new medical realms.Current gene therapy is not limited to the delivery of DNA only.Other therapeutic nucleic acid materials such as small interfering RNA, antisense oligonucleotides, or microRNA have also been included into the protocols of gene therapy.Nevertheless, it is increasingly clear that the success of gene therapy is dependent on the effectiveness of gene delivery, which is determined by the use of delivery vehicles, systems, or transferring techniques.Non-viral vectors, especially nanocarriers, have become a realistic alternative to viral vectorsassociated with some severe side effects (e.g., immunologenicity and carcinogenicity) for achieving better effieaey in gene therapy.Different types of nanocarriers such as liposomes, metallic and polymeric nanoparticles, dendrimers, gelatins, and quantum dots/rods have been developed, and each shows distinct characteristics.To provide an up-to-date and comprehensive summary on the nanocarriers of gene therapy, both the merits and drawbacks of the existing and emerging nanocarriers are compared and discussed in this review.Areas covered:Gene therapy can be defined as the transfer of nucleic acids to the somatic cells of an individual, resulting in expected therapeutic effects.To be specific, it is a novel therapeutic technique for the prevention, alleviation, compensation, or correction of gene-related diseases.Via the transfer of an exogenous gene or other genetic materials (e.g., a fragment of nucleic acid) into cells to correct genetic defects, express therapeutic gene products, or inactivate pathogenic genes, gene therapy can be utilized for treating cancers, infectious diseases, cardiovascular disorders, renal diseases, inner ear disorders, ophthalmologic and neurological pathologies, among others.Among various gene therapy protocols, gene correction or replacement is aimed at the in situ repair of a mutant or replacement with a normal gene.Gene augmentation or complementation refers to the addition of a functional copy of the gene to the cells that normally express the defected gene.Gene inactivation is applied if the diseased allele expresses a protein that either interferes with the protein product of the normal allele or shows a toxic effect.Thus, the goal of gene therapy is to extinguish the expression of the mutant allele.Furthermore, suicide gene therapy involves the use of a suicide gene, which is also called a drug-sensitive gene, to express an enzyme that can convert pro-drugs into cytotoxic substances, and it is an effective strategy to make cancer ceils more vulnerable to chemotherapy.Numerous gene transfer systems or gene vectors have been developed for making the gene transfer efficient, specific, and safe.An ideal vector should be specific to the target cells and easy to enter the cell body.It should be able to express abundantly and continuously.Furthermore, it has to hesafe, without showing any side effects, and be capable of large-scale production.The delivery vehicles, or carriers, of gene therapy encapsulate the therapeutic genes for delivery to the target cells.These vehicles include viral vectors (i.e., genetically disabled viruses) such as adenovirus, and nonviral vectors such as liposomes.Both viral and non-viral methods have been investigated, and each shows distinctive advantages and disadvantages.Viral carriers, including retrovirus (RV), adenovirus (AD), adeno-associated virus (AAV), and lentivirus (LV), normally exhibit a broad species and tissue tropism and require simple techniques for preparation and administration.They also show high transduction efficiency and long-term gene expression.However, they have a number of drawbacks, including high toxicity, immunogenicity, and mutagenicity, low target cell specificity, high cost, and unsuitability for transferring large-sized genes.Although nonviral delivery vehicles like nanocarriers seem to be less efficient than viral methods, they exhibit intrinsic advantages such as flexibility and safety.Nanoparticle complexes modified by functional molecules such as peptides, proteins, integrins, lectins, and antibodies have been developed for the generation of nanocarriers with low toxicity, high stability, and high cell specificity.Several varieties of nanoparticles (NPs) are availablefor use as nanocarriers, including polymeric NPs, dendrimers, inorganic or metal NPs, quantum dots (QDs), liposomes, and micelles.The versatility of polymeric nanocarriers offers a significant advantage to gene delivery over other nanocarrier platforms.Polymer matrices can be selected based on their utilities, allowing for the customization of nanoparticle properties.Additional advantages of polymeric nanocarriers include easy surface modification, high payload encapsulation efficiency, payload protection ability, large surface area-to-volume ratio, and the ability to modify the polymer erosion rate for temporal control on the release of nucleotides.Expert opinion: Gene therapy demonstrates a variety of advantages over conventional therapeutic modalities, such as its specificity or selectivity toward objects, minimal side effects, correction of genetic causes, and persistent therapeutic effects after single application.Nanocarriers for gene delivery have been widely utilized in all strategies of gene therapy, including gene correction, gene complementation, suicide gene therapy, and gene inactivation.The application of most combination therapies is inseparable from the development of effective nanovectors.Optimal gene transfer into various target cells still faces major obstacles, which include poor delivery efficiency, cellular toxicity, immunogenicity, oncogenicity, short-term transgenic expression, and low expression levels.Due to the distinct advantages of non-viral gene delivery methods, such as safety, high potential for targeting delivery, ability to transfer large-sized genes, low toxicity, ease in preparation, and low costs, numerous non-viral delivery systems have been developed and used in a broad range of studies during the past few years.Nevertheless, the methods developed thus far show limitations, including low transfection efficiency and poor transgene expression, which restrict their clinical applications.To date, many advanced nanomaterials have been used as non-viral gene delivery systems.While the in vitro and in vivo preclinical applications of advanced nanomaterials in gene therapy continue to grow, their nanotoxicology should be systematically examined prior to their translation into human bodies.Since the mechanism of intemalized NPs in inducing potential genotoxic effects such as mutagenicity, inflammatory response, and DNA damage still remains elusive,it is important to study the geno-compatibility and toxicogenomics of NPs for screening the compatible or useful delivery systems early in drug development.In principle, nanomaterials are able to enhance the delivery and improve the biological end-point of nucleic acids; however, they also show cytotoxicity that is dependent on the delivery system or target cells.Thus, the evaluation of transfection efficiency and assessment of safety are equivalently essential for gene transfer using these gene therapy vectors.Summary:Nanocarriers exhibit great potential for use as safe and potent gene delivery systems in a variety of clinical applications.Additional efforts should be made to address the aforementioned challenges faced by nanocarriers in gene therapy.These should specifically focus on the enhancement of transfection efficiency, reduction of toxicity, improvement of targeting specificity, and minimization of tissue damage.