Ribonuclease A-polymer conjugates via in situ growth for cancer treatment.

Efficient delivery of therapeutic proteins is a critical aspect for protein-based cancer treatment. Herein, an in situ growth approach was employed to prepare ribonuclease A (RNase A)-polymer conjugates by incorporating a cationic polymer, poly(N,N'-dimethylamino-2-ethyl methacrylate) (P(DMAEMA)), and a hydrophobic polymer, poly(N-isopropylacrylamide) (P(NIPAM)), through atom transfer radical polymerization (ATRP). The synthesized RNase A-polymer conjugates (namely R-P(D-b-N)) could preserve the integrity of RNase A and exhibit a unique combination of cationic and hydrophobic properties, leading to enhanced intracellular delivery efficiency. The successful delivery of RNase A by R-P(D-b-N) conjugates effectively triggered the cell apoptosis through the mitochondria-dependent signaling pathway to achieve the anti-proliferative response. Additionally, the conjugates could inhibit cell migration and thus possess the potential for the suppression of tumor metastasis. Overall, our findings highlight that the introduction of cationic and hydrophobic moieties via ATRP provides a versatile platform for the intracellular delivery of therapeutic proteins, offering a new avenue for treating diverse diseases.

A quaternary ammonium-based nanosystem enables delivery of CRISPR/Cas9 for cancer therapy.

Genome editing mediated by CRISPR/Cas9 is an attractive weapon for cancer therapy. However, in vivo delivery of CRISPR/Cas9 components to achieve therapeutic efficiency is still challenging. Herein, a quaternary ammonium-functionalized poly(L-lysine) and a cholesterol-modified PEG (QNP) were self-assembled with a negatively charged CRISPR Cas9/sgRNA ribonucleoprotein (RNP) to form a ternary complex (QNP/RNP). Such a delivery system of QNP exhibited multiplex genome editing capabilities in vitro (e.g., the GFP gene and the PLK1 gene). In addition, QNP/RNPPLK1 containing PLK1 sgRNA led to 30.99% of genome editing efficiency in MCF-7 cells with negligible cytotoxicity of the carrier. QNP/RNPPLK1, which was capable of simultaneously inhibiting cell proliferation, mediating cell cycle arrest and downregulating expression of PLK1, held great in vitro therapeutic efficiency. Moreover, QNP/RNPPLK1 exhibited outstanding accumulation in tumors and high biocompatibility in vivo. In an MCF-7 xenograft animal model, QNP/RNPPLK1 showed excellent anti-tumor efficacy and achieved 17.75% indels ratio. This work showcases the successful delivery of CRISPR Cas9/sgRNA RNP with enhanced genome editing efficiency and provides a potential on-demand strategy for cancer therapy.

Gram-scale preparation of quercetin supramolecular nanoribbons for intestinal inflammatory diseases by oral administration.

Gastrointestinal (GI) tract, which possesses the largest surface area of mucosa in the body, is easily suffered from inflammatory damages under the exposure of external stimulations. Excessive reactive oxygen species (ROS) production and continuous oxidative stress in intestines can elicit local mucosal injury, accelerate mucosal ulceration, and amplify the inflammatory response. Thereby, antioxidant therapy is a potential strategy against intestinal inflammatory diseases. Herein, we demonstrate the gram-scale preparation of quercetin supramolecular nanoribbons (SNRs) by using free quercetin molecules as the sole building block for preventing and treating intestinal inflammatory diseases. Unlike current clinical medicines, which mainly confront with poor response and severe adverse effects via bloodstream delivery, our quercetin SNRs possess an excellent antioxidant activity in the harsh environments of GI tract, a relative long retention time in GI tract, an admirable metabolism in GI tract without burdening other organs, and a specific adhesion to the inflamed intestinal epithelium via electrostatic interactions. These advantages strongly guarantee the applications of quercetin SNRs as oral medicines for intestinal inflammatory diseases. After establishing the models of intestinal inflammatory diseases caused by irradiation and drug stimulations, our quercetin SNRs exhibit the promising protective and therapeutic effects for radiation-induced acute enteritis and dextran sulfate sodium (DSS)-induced acute colitis. Because the super easy and fast preparation procedure and the nearly 100% loading capacity of quercetin SNRs, the current work provides a supramolecular nanomedicine with great clinical translation potential against intestinal inflammatory diseases.

Superoxide dismutase-embedded metal-organic frameworks via biomimetic mineralization for the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by chronic and spontaneous inflammation in the gastrointestinal tract, and has been associated with an improved level of reactive oxygen species (ROS). Herein, superoxide dismutase (SOD) was encapsulated into zeolitic imidazolate framework-zni (ZIF-zni) to construct a nanocomposite termed SOD@ZIF-zni through biomimetic mineralization, which was then used as a formulation for the IBD treatment. The SOD@ZIF-zni composite could efficiently suppress the level of ROS and pro-inflammatory cytokines, using the colorectal cancer cell line SW480 as a model. Oral administration of the SOD@ZIF-zni composite could relieve the oxidative stress and inhibit the release of pro-inflammatory cytokines in the inflamed colonic tissues, leading to the alleviation of colitis in dextran sulfate sodium-induced colitis mice. Overall, the favorable therapeutic efficacy and biocompatibility of SOD@ZIF-zni gave it potential to be used as a safe and effective formulation for IBD treatment in the future.

Genome editing of PD-L1 mediated by nucleobase-modified polyamidoamine for cancer immunotherapy.

Immune checkpoint blockade therapy against programmed death protein-1 and its ligand (PD-1/PD-L1) has been accepted as a promising approach to activate the immune system's anti-tumor response. Although small interfering RNA (siRNA) or antibodies can block the PD-1/PD-L1 pathway, the effect of this blockade is temporary and reversible. Here, we developed a nano-delivery system to achieve permanent disruption of the PD-L1 gene based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9) gene editing technology. In this system, the CRISPR/Cas9 plasmid was delivered into melanoma B16F10 cells using a nucleobase-modified polyamidoamine (PAMAM) derivative namely AP-PAMAM, which was constructed through the modification with 2-amino-6-chloropurine. Meanwhile, the carrier could efficiently facilitate the endosomal escape of CRISPR/Cas9 plasmid and thereby inhibit PD-L1 expression in cancer cells. Moreover, the intravenous injection of AP-PAMAM/plasmid nanoparticles could recruit and activate CD8+ T cells at the tumor site, promoting the secretion of cytokines and the killing of tumor cells. Overall, this nano-delivery system for genome editing provided a promising strategy to block the PD-1/PD-L1 pathway and obtain effective tumor immunotherapy.

Phenylboronic Acid-Modified Polyamidoamine Mediated the Transfection of Polo-Like Kinase-1 siRNA to Achieve an Anti-Tumor Efficacy.

BACKGROUND: The construction of tumor-targeting carriers with favorable transfection efficiency was of great significance to achieve the tumor gene therapy. The phenylboronic acid-modified polyamidoamine (namely PP) was employed as a carrier for the delivery of Polo-like kinase-1 siRNA (siPlk-1), inducing an obvious anti-tumor response. MATERIALS AND METHODS: The interaction between PP and siPlk-1 was evaluated by gel retardation assay. The transfection efficiency and tumor-targeting ability were analyzed by flow cytometry and confocal laser scanning microscopy, using hepatocarcinoma cell line HepG2 as a model. The anti-proliferation effect of PP/siPlk-1 and related mechanism were studied using the strategies of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis and cell cycle arrest. The anti-migration effect induced by PP/siPlk-1 delivery was assayed by wound healing and Transwell migration techniques. Finally, quantitative real-time PCR and Western blotting were performed to measure the expression level of Plk-1 and other key targets. RESULTS: The derivative PP could achieve the condensation of siPlk-1 into stable nanoparticles at nitrogen/phosphate groups ratio (N/P ratio) of >3.0, and it could facilitate the transfection of siPk-1 in a phenylboronic acid-dependent manner. The PP/siPlk-1 nanoparticles exhibited obvious anti-proliferation effect owing to the gene silence of Plk-1, which was identified to be associated with the cell apoptosis and cell cycle arrest at G2 phase. Meanwhile, PP/siPlk-1 transfection could efficiently suppress the migration and invasion of tumor cells. CONCLUSION: The derivative PP has been demonstrated to be an ideal tumor-targeting carrier for the delivery of Plk-1 siRNA, exhibiting great potential in the gene therapy of malignant tumors.

Lipoic Acid-Modified Oligoethyleneimine-Mediated miR-34a Delivery to Achieve the Anti-Tumor Efficacy.

MiR-34a, an important tumor suppressor, has been demonstrated to possess great potential in tumor gene therapy. To achieve the upregulation of miR-34a expression level, an oligoethyleneimine (OEI) derivative was constructed and employed as the carrier through the modification with lipoic acid (LA), namely LA-OEI. In contrast to OEI, the derivative LA-OEI exhibited superior transfection efficiency measured by confocal laser scanning microscopy and flow cytometry, owing to rapid cargo release in the disulfide bond-based reduction sensitive pattern. The anti-proliferation and anti-migration effects were tested after the miR-34a transfection to evaluate the anti-tumor response, using human cervical carcinoma cell line HeLa as a model. The delivery of LA-OEI/miR-34a nanoparticles could achieve obvious anti-proliferative effect caused by the induction of cell apoptosis and cell cycle arrest at G1 phase. In addition, it could inhibit the migration of tumor cells via the downregulation of MMP-9 and Notch-1 level. Overall, the LA-OEI-mediated miR-34a delivery was potential to be used as an effective way in the tumor gene therapy.

Artesunate-loaded porous PLGA microsphere as a pulmonary delivery system for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) has emerged to be a significant cause of cancer mortality worldwide. Artesunate (ART) extracted from Chinese herb Artemisia annua L, has been proven to possess desirable anti-cancer efficacy, especially for the metastatic NSCLC treatment. Moreover, the poly(lactic-co-glycolic acid) (PLGA) microsphere has been considered to be a potential pulmonary delivery system for the sustained drug release to enhance the therapeutic efficacy of lung cancer. Herein, the ART-loaded porous PLGA microsphere was prepared through the emulsion solvent evaporation approach. The microsphere was demonstrated to possess highly porous structure and ideal aerodynamic diameter for the pulmonary administration. Meanwhile, sustained ART release was obtained from the porous microsphere within 8 days. The release solution collected from the microsphere could be effectively uptake by the cells and further induce the cell apoptosis and the cell cycle arrest at G2/M phase to execute the anti-proliferative effect, using human lung adenocarcinoma cell line A549 as a model. Additionally, strong inhibitory effect on the cell migration and invasion could be obtained after the treatment with release solution. Taken together, our results demonstrated that the ART-loaded PLGA porous microsphere could achieve excellent anti-cancer efficacy, providing a potential approach for the NSCLC treatment via the pulmonary administration.

Dual ATP/reduction-responsive polyplex to achieve the co-delivery of doxorubicin and miR-23b for the cancer treatment.

Combination therapy based on the co-delivery of therapeutic genes and anti-cancer drugs has emerged as a promising approach in the cancer treatment, and stimuli-responsive delivery systems could further improve the therapeutic efficacy. Herein, an ATP aptamer and its complementary DNA were used to form Duplex into which doxorubicin (DOX) was loaded to construct DOX-Duplex, and then the lipoic acid-modified oligoethyleneimine (LA-OEI) was employed as a carrier to realize the co-delivery of DOX-Duplex and miR-23b. The ternary nanocomplex LA-OEI/miR-23b/DOX-Duplex showed excellent anti-proliferative effect by inducing the cell apoptosis via mitochondrial signaling pathway and arresting the cell cycle at S phase. Meanwhile, the co-delivery of DOX-Duplex and miR-23b could efficiently inhibit the metastasis of cancer cells by reducing the expression level of MMP-9. The favorable anti-tumor efficacy of ternary nanocomplex was attributed to the rapid drug release in response to intracellular ATP concentration and reduction conditions and the synergistic effect between DOX-Duplex and miR-23b. Thus, ATP aptamer and reduction-responsive polymer provided a convenient platform to construct dual stimuli-responsive systems for the co-delivery of gene and drug in the cancer treatment.

Nucleolin-Targeting AS1411 Aptamer-Modified Micelle for the Co-Delivery of Doxorubicin and miR-519c to Improve the Therapeutic Efficacy in Hepatocellular Carcinoma Treatment.

BACKGROUND: Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters. The combination of gene therapy and chemotherapy has been considered as a potential approach to improve the anti-cancer efficacy by reversing the MDR effect. MATERIALS AND METHODS: The AS1411 aptamer-functionalized micelles were constructed through an emulsion/solvent evaporation strategy for the simultaneous co-delivery of doxorubicin and miR-519c. The therapeutic efficacy and related mechanism of micelles were explored based on the in vitro and in vivo active targeting ability and the suppression of MDR, using hepatocellular carcinoma cell line HepG2 as a model. RESULTS: The micelle was demonstrated to possess favorable cellular uptake and tumor penetration ability by specifically recognizing the nucleolin in an AS1411 aptamer-dependent manner. Further, the intracellular accumulation of doxorubicin was significantly improved due to the suppression of ABCG2-mediated drug efflux by miR-519c, resulting in the efficient inhibition of tumor growth. CONCLUSION: The micelle-mediated co-delivery of doxorubicin and miR-519c provided a promising strategy to obtain ideal anti-cancer efficacy through the active targeting function and the reversion of MDR.

Reactive Oxygen Species-Mediated Inflammation and Apoptosis in Hand-Foot Syndrome Induced by PEGylated Liposomal Doxorubicin.

BACKGROUND: Doxil® (PEGylated liposomal doxorubicin, PLD) has been widely used in cancer treatment due to its excellent therapeutic efficacy, but it can simultaneously cause severe adverse effects such as hand-foot syndrome (HFS). To date, the pathophysiologic mechanism of HFS development induced by PLD administration has not been well understood. MATERIALS AND METHODS: The histological features of skin lesion in PLD-induced HFS model were characterized by hematoxylin and eosin (H&E) staining and picrosirius red staining, and the induction of inflammation and apoptosis in the epidermal layer was detected by immunohistochemical and TUNEL staining. Moreover, the generation of reactive oxygen species (ROS) was determined to elucidate the potential mechanism of skin lesion in the development of HFS. RESULTS: The administration of PLD has been demonstrated to induce the histological damage of skin tissues including the destruction of collagen fibers and the induction of severe inflammation and apoptosis of epidermal cells. The mechanism was probably attributed to the accumulation of PLD in the skin tissues during the long-term circulation and further the induction of ROS to cause the oxidative damage of keratinocytes owing to the sustained release of doxorubicin from PLD. CONCLUSION: The ROS generation induced by the administration of PLD has been identified to be a crucial factor in the development of HFS, which could be used as a potential therapeutic target to alleviate the HFS symptom of PLD administration.

N-Isopropylacrylamide-modified polyethylenimine-mediated miR-29a delivery to inhibit the proliferation and migration of lung cancer cells.

MicroRNAs have been identified as a promising tool in cancer gene therapy, and an efficient and safe gene carrier was significantly required in the clinical application of miRNAs. Herein, a polyethylenimine (PEI) derivative, N-isopropylacrylamide-modified PEI (namely PEN), was constructed through Michael addition and then employed as a carrier for miR-29a transfection. The carrier PEN has been demonstrated to possess favorable ability to condense miR-29a into stable nanoparticles and protect miR-29a against the nuclease degradation, using agarose gel retardation assay. Meanwhile, PEN exhibited excellent efficiency in miR-29a transfection demonstrated by flow cytometry and confocal laser scanning microscope. Further, the PEN-mediated miR-29a transfection could achieve an obvious anti-proliferative effect owing to the activation of cell apoptosis and the cell cycle arrest at G1 phase, using human lung adenocarcinoma cell line A549 as a model. In addition, PEN/miR-29a nanoparticles could suppress the migration and invasion of cancer cells measured by wound healing and Transwell migration assays. Overall, the PEN-mediated miR-29a transfection could be potentially employed as a useful approach to achieve cancer gene therapy.

A genipin-crosslinked protein-polymer hybrid system for the intracellular delivery of ribonuclease A.

BACKGROUND: Therapeutic proteins have been widely used in the treatment of various diseases, and effective carriers are highly required for achieving protein delivery to obtain favorable treatment potency. MATERIALS AND METHODS: A protein-polymer hybrid system was constructed through the genipin-mediated crosslinking of polyethyleneimine with a weight-average molecular weight of 25,000 g/mol (PEI25K) and ribonuclease A (RNase A), namely RGP. RESULTS: The RGP nanoparticles were observed to be easily internationalized in HeLa cells owing to the introduction of positively charged PEI25K, thereby triggering the antiproliferative effects by cleaving RNA molecules in the tumor cells. Moreover, red fluorescence could be obviously visualized in the tumor cells after RGP delivery, which was attributed to the intrinsic characteristics of genipin. CONCLUSION: The protein-polymer hybrid system prepared via the genipin-mediated crosslinking has exhibited potential to be used as a theranostic platform for both in vivo imaging and delivering diverse therapeutic proteins.

Inhibition of proliferation and migration of tumor cells through phenylboronic acid-functionalized polyamidoamine-mediated delivery of a therapeutic DNAzyme Dz13.

BACKGROUND: The phenylboronic acid-functionalized polyamidoamine (PP) was employed as a gene carrier for Dz13 delivery, inducing an obvious anticancer response. MATERIALS AND METHODS: The Dz13 condensation ability of PP was evaluated through gel retardation assay. The cellular uptake mechanism of PP/Dz13 nanoparticles was studied using confocal laser scanning microscope and flow cytometer. The inhibition ability of cell proliferation, migration and invasion was investigated through MTT assay, flow cytometry, wound healing and Transwell migration assays, using hepatocarcinoma cell line HepG2 as a model. Finally, Western blotting analysis was used to detect the signaling pathway associated with the inhibition of cell apoptosis and migration induced by Dz13 delivery. RESULTS: The carrier PP could efficiently condense Dz13 into stable nanoparticles at mass ratios of >1.5. The hydrodynamic diameter and zeta potential of PP/Dz13 nanoparticles were measured to be 204.77 nm and +22.00 mV at a mass ratio of 10.0, respectively. The nanoparticles could realize an efficient cellular uptake in sialic acid-dependent endocytosis manner. Moreover, the nanoparticles exhibited an obvious antiproliferation effect through the induction of cell apoptosis and cell cycle arrest due to the cleavage of c-Jun mRNA. Besides, the suppression of cell migration and invasion could be achieved after the PP/Dz13 transfection, attributing to the decreased expression level of MMP-2 and MMP-9. CONCLUSION: The PP provided a potential delivery system to achieve the tumor-targeting gene therapy.

Phenylboronic acid-modified polyamidoamine-mediated delivery of short GC rich DNA for hepatocarcinoma gene therapy.

Phenylboronic acid was introduced on the surface of polyamidoamine to construct a derivative PP, which was further used as a tumor-targeting carrier for realizing the delivery of short GC rich DNA (GCD). The PP-mediated GCD delivery could disrupt the polymerization of microtubules and thus trigger a strong anti-proliferative effect through the induction of cell apoptosis and cell cycle arrest, using hepatocellular carcinoma cell line HepG2 as a model. In addition, the transfection of PP/GCD nanoparticles could efficiently suppress cell migration and invasion. Moreover, the intravenous injection of PP/GCD nanoparticles could dramatically decrease the tumor growth by inducing the in situ apoptosis of the tumor and meanwhile it exhibited a desirable safety profile. Overall, the development of tumor-targeting carrier PP will provide a promising platform for GCD delivery to obtain an anti-cancer efficacy which is beneficial for facilitating tumor gene therapy in future clinical applications.

A chemoenzymatically synthesized cholesterol-g-poly(amine-co-ester)-mediated p53 gene delivery for achieving antitumor efficacy in prostate cancer.

BACKGROUND: An amphiphilic cationic copolymer cholesterol-g-poly(amine-co-ester), namely Chol-g-PMSC-PPDL synthesized in a chemoenzymatic route has been utilized as a carrier for p53 gene delivery to check its antitumor efficacy, using human prostate cancer cell line PC-3 (p53 null) as a model. MATERIALS AND METHODS: The transfection efficiency was measured by quantitative PCR and Western blotting assay. The anti-proliferative effect was detected using MTT method, colony formation assay and Live/Dead staining. The anti-migration effect was evaluated through wound healing and Transwell migration assays. RESULTS: The transfection efficiency assay indicated that the carrier-mediated p53 gene transfection could dramatically enhance the intracellular p53 expression level. Through p53 gene delivery, obvious anti-proliferative effect could be detected which was elucidated to be associated with the simultaneous activation of mitochondrial-dependent apoptosis pathway and cell cycle arrest at G1 phase. Meanwhile, the anti-migration effect could be obtained after p53 gene transfection. CONCLUSION: Chol-g-PMSC-PPDL-mediated p53 gene transfection could potentially be employed as a promising strategy for achieving effective anti-tumor response.

Phenylboronic acid-functionalized polyamidoamine-mediated miR-34a delivery for the treatment of gastric cancer.

In the present research, a tumor-targeted gene carrier, PPP, was constructed through the modification of phenylboronic acid onto the surface of a polyamidoamine dendrimer, and then miR-34a delivery was employed as a model to evaluate its anti-tumor efficacy. The carrier PPP was identified to possess favorable miR-34a binding and condensation ability and meanwhile protect miR-34a against nuclease degradation. Through confocal laser scanning microscopy and flow cytometry analysis, PPP-mediated cellular uptake of miR-34a was found to proceed through a sialic acid-dependent endocytosis pathway and the nanoparticles could achieve endosome/lysosome escape within 6 h. Further, an anti-proliferative effect could be obtained after PPP/miR-34a transfection through the induction of cell apoptosis. Meanwhile, the inhibition of migration and invasion could be realized through blocking the Notch-1 signaling pathway after PPP/miR-34a treatment. Finally, PPP possessed acceptable safety and inhibited in vivo tumor growth through the in situ apoptosis of tumor sites, which relied on the specific tumor-targeting ability and long circulation time in the blood. In summary, the derivative PPP could be potentially utilized as an efficient carrier for miR-34a delivery to achieve an anti-tumor response in clinical use.

Nano-Scaled Zeolitic Imidazole Framework-8 as an Efficient Carrier for the Intracellular Delivery of RNase A in Cancer Treatment.

BACKGROUND: Zeolitic imidazole framework-8 (ZIF-8) as an emerging platform has exhibited great potential in the protein delivery owing to its tunable chemical functionality. MATERIALS AND METHODS: ZIF-8 was employed as a carrier for the encapsulation and intracellular delivery of RNase A, aimed to achieve a rapid release of proteins in an acidic environment. The intracellular uptake of RNase A was studied by confocal laser scanning microscopy (CLSM), and the inhibition of cell proliferation after the delivery of RNase A was evaluated by MTT assay, Live/Dead staining, and TUNEL cell apoptosis analysis, using human lung adenocarcinoma cell line A549 as a model. The biocompatibility of RNase A@ZIF-8 nanoparticles was systematically detected through the hemolysis and cytotoxicity assay. RESULTS: The RNase A@ZIF-8 nanoparticles constructed by biomimetic mineralization could not only facilitate the encapsulation of protein molecules (protein loading: 13.4%) but also maintain the enzymatic activity and stability of RNase A. The CLSM images showed that RNase A@ZIF-8 nanoparticles could efficiently improve the intracellular uptake of RNase A. Moreover, RNase A@ZIF-8 nanoparticles could obviously inhibit the cell proliferation through the induction of cell apoptosis, with 31.3% of cell death at an RNase A concentration of 10 µg/mL. Finally, RNase A@ZIF-8 nanoparticles were elucidated to possess excellent biocompatibility, with hemolysis of <5% using the same concentration of RNase A@ZIF-8. CONCLUSION: ZIF-8 could be used as an effective carrier to deliver the therapeutic protein RNase A into the cytosol, which will be beneficial for improving the efficacy of cancer treatment.

A comprehensive review on histone-mediated transfection for gene therapy.

Histone has been considered to be an effective carrier in non-viral gene delivery due to its unique properties such as efficient DNA binding ability, direct translocation to cytoplasm and favorable nuclear localization ability. Meanwhile, the rapid development of genetic engineering techniques could facilitate the construction of multifunctional fusion proteins based on histone molecules to further improve the transfection efficiency. Remarkably, histone has been demonstrated to achieve gene transfection in a synergistic manner with cationic polymers, affording to a significant improvement of transfection efficiency. In the review, we highlighted the recent developments and future trends in gene delivery mediated by histones or histone-based fusion proteins/peptides. This review also discussed the mechanism of histone-mediated gene transfection and provided an outlook for future therapeutic opportunities in the viewpoint of transfection efficacy and biosafety.