Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity. Currently, gene therapy drugs such as siRNA, shRNA, antisense oligonucleotide, CRISPR/Cas9 system, plasmid DNA and miRNA have shown great potential in biomedical applications. To avoid the degradation of gene therapy drugs in the body and effectively deliver them to target tissues, cells and organelles, the development of excellent drug delivery vehicles is of utmost importance. Viral vectors are the most widely used delivery vehicles for gene therapy in vivo and in vitro due to their high transfection efficiency and stable transgene expression. With the development of nanotechnology, novel nanocarriers are gradually replacing viral vectors, emerging superior performance. This review mainly illuminates the current widely used gene therapy drugs, summarizes the viral vectors and non-viral vectors that deliver gene therapy drugs, and sums up the application of gene therapy to treat genetic diseases. Additionally, the challenges and opportunities of the field are discussed from the perspective of developing an effective nano-delivery system.

Due to its high therapeutic efficiency and low systemic toxicity, natural bioactive curcumin has attracted more and more attention as a potential antineoplastic drug. Although the emergence of a carrier-free nanocrystalline technology could improve the solubility and guarantee the high drug loading of curcumin, uncontrollable drug release and fast systemic metabolism are definite obstacles that hinder its further application in cancer treatment. Here, hyaluronic acid (HA) modification was carried out on the surface of curcumin nanocrystals (Cur-NC) to obtain surface reformed hydrophilic HA@Cur-NCs that exhibit prolonged biodistribution. Besides this, HA@Cur-NC shows enhanced intracellular uptake in CD44 overexpressing MDA-MB-231 cells, but reduced uptake when pre-treated with HA. The apoptotic effects, confirmed by flow cytometry, suggest that HA@Cur-NC could achieve high anticancer activity against MDA-MB-231 cells. In vivo pharmacokinetic studies suggest that the t_1/2 and mean residence time (MRT) of Cur are significantly extended after the intravenous administration of HA@Cur-NC in normal rats. Moreover, HA@Cur-NC demonstrated superior anticancer effects in a murine 4T1 orthotopic breast cancer model compared with free drug and Cur-NC. Overall, these results show the potential of HA@Cur-NC as a suitable formula for use in breast cancer therapy.

The fabrication of aptamers on DNA nanostructures through the DNA origami method has shown great potential for in vitro and in vivo tumor targeting delivery. Herein, tetrahedral multivalent DNA (Td) nanocages modified with different numbers of MUC1-aptamers (nApt-Td) were obtained via the self-assembly of nucleic acid backbones containing the aptamer DNA fragment without complicated chemical modification steps. Then, doxorubicin (DOX) was encapsulated in the modified nApt-Td nanocages via non-covalent interactions. Due to the specific identification of the aptamers, the intracellular uptake studies demonstrated that the multivalent modified aptamers on the vertex of Td significantly enhanced the intracellular uptake efficiency in MCF-7 tumor cells, but reduce that of normal cells. The number of aptamers had a significant influence on the intracellular uptake efficiency of Td nApt-Td. Furthermore, improved in vivo systemic safety and decreased systemic toxicity accompanied with effective tumor inhibition were also demonstrated compared with the anti-tumor efficiency of free DOX.

Mesenchymal stem cells (MSC) are particularly effective in promoting cartilage regeneration due to their immunomodulatory, anti-inflammatory and regenerative repair functions of tissues and organs. Meanwhile, the intra-articular delivery and synergy with other therapeutic drugs have been the key issues driving their further application. We report a mussel-inspired multifunctional hydrogel system, which could achieve co-delivery and synergism effect of MSC-derived exosomes (Exos) with icariin (ICA). The ICA and Exos co-delivered articular cavity injection system are expected to retain in the joint cavity and promote cartilage regeneration, due to the thermosensitive, self-healing and adhesion properties of the mussel-inspired multifunctional hydrogel. The experimental results proved that Exos enhanced the cellular uptake of ICA by more than 2-fold evenly, and the synergism of Exos and ICA efficiently improve the cell proliferation and migration. After synergic treatment, the content of matrix metalloproteinase 13 in the supernatant and intracellular decreased by 47% and 59%, respectively. In vivo study, ICA-loaded Exos exhibited prolonged retention behavior by multifunctional hydrogel delivery, thus displayed an increased cartilage protection. In the model of osteoarthritis, co-delivery hydrogel system relieved the cartilage recession, ensuring appropriate cartilage thickness.

Hypoxic tumor microenvironment (TME) is the major contributor to cancer metastasis, resistance to chemotherapy, and recurrence of tumors. So far, no approved treatment has been available to overcome tumor hypoxia. The present study aimed to relieve tumor hypoxia via a nanozyme theranostic nanomaterial as well as providing magnetic resonance imaging (MRI)-guided therapy. Manganese dioxide (MnO₂) was used for its intrinsic enzymatic activity co-loaded with the anti-cancer drug Doxorubicin (Dox) within the recombinant heavy-chain apoferritin cavity to form MnO₂-Dox@HFn. Following the synthesis of the nanomaterial, different characterizations were performed as well as its nanozyme-like ability. This nanoplatform recognizes tumor cells through the transferrin receptors 1 (TfR1) which are highly expressed on the surface of most cancer cells. The cellular uptake was confirmed by flow cytometry and fluorescence spectroscopy. In vitro and in vivo studies have been investigated to evaluate the hypoxia regulation, MRI ability and anti-tumor activity of MnO₂-Dox@HFn. Being a TME-responsive nanomaterial, MnO₂-Dox@HFn exerted both peroxidase and catalase activity that mainly produce massive oxygen and Mn²⁺ ions. Respectively, these products relieve the unfavorable tumor hypoxia and also exhibit T1-weighted MRI with a high longitudinal relaxivity of 33.40 mM. s⁻¹. The utility of MnO₂-Dox@HFn was broadened with their efficient anti-cancer activity proved both in vitro and in vivo. MnO₂-Dox@HFn successfully overcome tumor hypoxia with double potentials enzymatic ability and diagnostic capacity. This investigation could ignite the future application for cancer theranostic nanozyme therapy.