Albumin Nanoparticles Increase the Efficacy of Doxorubicin Hydrochloride Liposome Injection Based on Threshold Theory.

One of the most significant reasons hindering the clinical translation of nanomedicines is the rapid clearance of intravenously injected nanoparticles by the mononuclear phagocyte system, particularly by Kupffer cells in the liver, leading to an inefficient delivery of nanomedicines for tumor treatment. The threshold theory suggests that the liver's capacity to clear nanoparticles is limited, and a single high dose of nanoparticles can reduce the hepatic clearance efficiency, allowing more nanomedicines to reach tumor tissues and enhance therapeutic efficacy. Building upon this theory, researchers have conducted numerous validation studies based on the same nanoparticle carrier systems. These studies involve the use of albumin nanoparticles to improve the therapeutic efficacy of albumin nanomedicines as well as polyethylene glycol (PEG)-modified liposomal nanoparticles to enhance the efficacy of PEGylated liposomal nanomedicines. However, there is no research indicating the feasibility of the threshold theory when blank nanoparticles and nanomedicine belong to different nanoparticle carrier systems currently. In this study, we prepared two different sizes of albumin nanoparticles by using bovine serum albumin. We used the marketed nanomedicine liposomal doxorubicin hydrochloride injection (trade name: LIBOD, manufacturer: Shanghai Fudan-zhangjiang Biopharmaceutical Co., Ltd.), as the representative nanomedicine. Through in vivo experiments, we found that using threshold doses of albumin nanoparticles still can reduce the clearance rate of LIBOD, prolong its time in vivo, increase the area under the plasma concentration-time curve (AUC), and also lead to an increased accumulation of the drug at the tumor site. Furthermore, evaluation of in vivo efficacy and safety further indicates that threshold doses of 100 nm albumin nanoparticles can enhance the antitumor effect of LIBOD without causing harm to the animals. During the study, we found that the particle size of albumin nanoparticles influenced the in vivo distribution of the nanomedicine at the same threshold dose. Compared with 200 nm albumin nanoparticles, 100 nm albumin nanoparticles more effectively reduce the clearance efficiency of LIBOD and enhance nanomedicine accumulation at the tumor site, warranting further investigation. This study utilized albumin nanoparticles to reduce hepatic clearance efficiency and enhance the delivery efficiency of nonalbumin nanocarrier liposomal nanomedicine, providing a new avenue to improve the efficacy and clinical translation of nanomedicines with different carrier systems.

Marine biomaterials in biomedical nano/micro-systems.

Marine resources in unique marine environments provide abundant, cost-effective natural biomaterials with distinct structures, compositions, and biological activities compared to terrestrial species. These marine-derived raw materials, including polysaccharides, natural protein components, fatty acids, and marine minerals, etc., have shown great potential in preparing, stabilizing, or modifying multifunctional nano-/micro-systems and are widely applied in drug delivery, theragnostic, tissue engineering, etc. This review provides a comprehensive summary of the most current marine biomaterial-based nano-/micro-systems developed over the past three years, primarily focusing on therapeutic delivery studies and highlighting their potential to cure a variety of diseases. Specifically, we first provided a detailed introduction to the physicochemical characteristics and biological activities of natural marine biocomponents in their raw state. Furthermore, the assembly processes, potential functionalities of each building block, and a thorough evaluation of the pharmacokinetics and pharmacodynamics of advanced marine biomaterial-based systems and their effects on molecular pathophysiological processes were fully elucidated. Finally, a list of unresolved issues and pivotal challenges of marine-derived biomaterials applications, such as standardized distinction of raw materials, long-term biosafety in vivo, the feasibility of scale-up, etc., was presented. This review is expected to serve as a roadmap for fundamental research and facilitate the rational design of marine biomaterials for diverse emerging applications.

Modulation of Aggregation-Caused Quenching to Aggregation-Induced Emission: Finding a Biocompatible Polymeric Theranostics Platform for Cancer Therapy.

Dual intramolecular FRET polymers are synthesized via Suzuki coupling and their luminescence characteristics from aggregation-caused quenching (ACQ) to aggregation-induced emission (AIE) is modulated conveniently by adjusting the charged ratios. The finally obtained AIE polymer is further employed to construct doxorubicin loaded nanoparticles as a promising theranostics platform for cancer therapy.

Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)-Glycyrrhetinic Acid Nanoparticles To Induce Autophagy-Mediated Liver Cancer Combination Therapy.

Combination therapy has been developed as a promising therapeutic approach for hepatocellular carcinoma therapy. Here we report a low toxicity and high performance nanoparticle system that was self-assembled from a poly(ethylenimine)-glycyrrhetinic acid (PEI-GA) amphiphilic copolymer as a versatile gene/drug dual delivery nanoplatform. PEI-GA was synthesized by chemical conjugation of hydrophobic GA moieties to the hydrophilic PEI backbone via an acylation reaction. The PEI-GA nanocarrier could encapsulate doxorubicin (DOX) efficiently with loading level about 12% and further condense DNA to form PEI-GA/DOX/DNA complexes to codeliver drug and gene. The diameter of the complexes is 102 ± 19 nm with zeta potential of 19.6 ± 0.2 mV. Furthermore, the complexes possess liver cancer targeting ability and could promote liver cancer HepG2 cell internalization. Apoptosis of cells could be induced by chemotherapy of DOX, and PI3K/Akt/mTOR signaling pathway acts a beneficial effect on the modulation of autophagy. Here, it is revealed that utilizing PEI-GA/DOX/shAkt1 complexes results in effective autophagy and apoptosis, which are useful to cause cell death. The induction of superfluous autophagy is reported to induce type-II cell death and also could increase the sensity of chemotherapy to tumor cells. In this case, combining autophagy and apoptosis is meaningful for oncotherapy. In this study, PEI-GA/DOX/shAkt1 has demonstrated favorable tumor target ability, little side effects, and ideal antitumor efficacy.

Liposome Loaded Ion/Temperature Dual Responsive Gellan Gum Hydrogel as Potential Nasal-To-Brain Delivery System.

Intranasal administration, which can bypass the blood-brain barrier (BBB), is widely recognized as a promising strategy for high-efficiency drug delivery to the brain. Herein, for the purpose of effectively delivering drugs to the brain via intranasal administration, glutathione (GSH)-modified gellan gum (GSH-GG) with ion/temperature dual responsive properties was synthesized and encapsulated on galanthamine hydrobromide (GH)-loaded liposomes (GH-Lipo) for effective GH delivery to the brain (GH-Lipo@GSH-GG). Our results demonstrated that GSH-GG greatly decreased the gelation temperature of GG from 44.0 °C to 22.1 °C without compromising its ion responsiveness. Moreover, GSH-GG had a good protection ability for GH-loaded liposomes without affecting its drug release. Most importantly, the finally obtained GH-Lipo@GSHGG showed acceptable targeted delivery of GH to the brain upon in vivo administration. Therefore, this formulation can be employed as a potential delivery system in nasal-to-brain delivery.

Small Molecule Modifications Significantly Increase the Transfection Efficiency of Low-Molecular Polymer.

Gene vectors with high biocompatibility and transfection efficiency are critical for successful gene therapy. PEI 25K (Polyethyleneimine 25K) is a common polymeric gene vector that has been employed as a positive control material in gene transfection studies due to its good performance in endosome escape. PEI 25K's indegradability and abundance of positive charges, on the other hand, cause toxicity in cells, limiting its use. In this study, we developed the PEI-ER non-viral vector by adding an endoplasmic reticulum (ER) targeting ligand to low molecular weight PEI 1.8K. These small molecule modifications dramatically improved PEI transfection efficiency while barely interfering with compatibility. PEI-ER/DNA complexes were discovered to enter the cell via caveolin-mediated endocytosis, avoiding destruction in the endosome. We believe that this little chemical alteration is a simple solution to enhance the efficacy of cationic polymer vectors in gene transport, and it has a lot of medicinal applications.

Silica-Coated Fe3O4 Nanoparticles as a Bifunctional Agent for Magnetic Resonance Imaging and ZnII Fluorescent Sensing.

Bifunctional magnetic/fluorescent core-shell silica nanospheres (MNPs) encapsulated with the magnetic Fe3O4 core and a derivate of 8-amimoquinoline (N-(quinolin-8-yl)-2-(3-(triethoxysilyl) propylamino) acetamide) (QTEPA) into the shell were synthesized. These functional MNPs were prepared with a modified stöber method and the formed Fe3O4@SiO2-QTEPA core-shell nanocomposites are biocompatible, water-dispersible, and stable. These prepared nanoparticles were characterized by X-ray power diffraction (XRD), transmission electron microscopy (TEM), thermoelectric plasma Quad II inductively coupled plasma mass spectrometry (ICP-MS), superconducting quantum interference device (SQUID), TG/DTA thermal analyzer (TGA) and Fourier transform infrared spectroscopy (FTIR). Further application of the nanoparticles in detecting Zn2+ was confirmed by the fluorescence experiment: the nanosensor shows high selectivity and sensitivity to Zn2+ with a 22-fold fluorescence emission enhancement in the presence of 10 µM Zn2+. Moreover, the transverse relaxivity measurements show that the core-shell MNPs have T2 relaxivity (r2) of 155.05 mM-1 S-1 based on Fe concentration on the 3.0 T scanner, suggesting that the compound can be used as a negative contrast agent for MRI. Further in vivo experiments showed that these MNPs could be used as MRI contrast agent. Therefore, the new nanosensor provides the dual modality of magnetic resonance imaging and optical imaging.

Pathologically Responsive Mitochondrial Gene Therapy in an Allotopic Expression-Independent Manner Cures Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON) is a rare inherited blindness caused by mutations in the mitochondrial DNA (mtDNA). The disorder is untreatable and tricky, as the existing chemotherapeutic agent Idebenone alleviates symptoms rather than overcoming the underlying cause. Although some studies have made progress on allotopic expression for LHON, in situ mitochondrial gene therapy remains challenging, which may simplify delivery procedures to be a promising therapeutic for LHON. LHON becomes more difficult to manage in the changed mitochondrial microenvironment, including increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP). Herein, a pathologically responsive mitochondrial gene delivery vector named [triphenylphosphine-terminated poly(sulfur-containing thioketal undecafluorohexylamine histamine) and Ide-terminated poly(sulfur-containing thioketal undecafluorohexylamine histamine)] (TISUH) is reported to facilitate commendable in situ mitochondrial gene therapy for LHON. TISUH directly targets diseased mitochondria via triphenylphosphine and fluorination addressing the decreasing MMP. In addition, TISUH can be disassembled by high mitochondrial ROS levels to release functional genes for enhancing gene transfection efficiency and fundamentally correcting genetic abnormalities. In both traditional and gene-mutation-induced LHON mouse models, TISUH-mediated gene therapy shows satisfactory curative effect through the sustained therapeutic protein expression in vivo. This work proposes a novel pathologically responsive in situ mitochondrial delivery platform and provides a promising approach for refractory LHON as well as other mtDNA mutated diseases treatments.

Antibacterial Photodynamic Gold Nanoparticles for Skin Infection.

Damage or injury to the skin creates wounds that are vulnerable to bacterial infection, which in turn retards the process of skin regeneration and wound healing. In patients with severe burns and those with chronic diseases, such as diabetes, skin infection by multidrug-resistant bacteria can be lethal. Therefore, a broad-spectrum therapy to effectively eradicate bacterial infection through a mechanism different from that of antibiotics is much sought after. We successfully synthesized antibacterial photodynamic gold nanoparticles (AP-AuNPs), which are self-assembled nanocomposites of an antibacterial photodynamic peptide and poly(ethylene glycol) (PEG)-stabilized AuNPs. The AP-AuNPs exhibited aqueous and light stability, a satisfactory generation of reactive oxygen species (ROS), and a remarkable antibacterial effect toward both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli upon light irradiation. Moreover, the synthesized nanocomposites significantly inhibited bacterial growth and biofilm formation in vitro. Photodynamic antibacterial treatment accelerated the wound-healing rate in S. aureus infections, mimicking staphylococcal skin infections. Using a combination of the bactericidal effect of a peptide, the photodynamic effect of a photosensitizer, and the multivalency clustering on AuNPs for maximal antibacterial effect under light irradiation, we synthesized AP-AuNPs as a wound-dressing nanomaterial in skin infections to promote wound healing. Our findings indicate a promising strategy in the management of bacterial infections resulting from damaged skin tissue, an aspect that has not been fully explored by our peers.

Dex-Aco coating simultaneously increase the biocompatibility and transfection efficiency of cationic polymeric gene vectors.

Cationic polymeric vectors attracted plenty of attentions in gene therapy due to nonimmunogenicity, easy to synthesis and flexible properties. However, biocompatibility challenge such as nonspecific interactions with blood cells and serum proteins, may affect the delivery efficiency of cationic vectors; besides, inefficient endosomal escape causes low transfection efficiency. Herein, we synthesized an anionic coating polymer dextran-g-aconic anhydride (Dex-Aco, DA) through a simple esterification reaction, which can protect cationic polymer poly(cystamine-bis-acrylamide)-agmatine-histamine (PCAH, PC) constructed nanomedicine against interactions with blood cells and serum proteins, improving biocompatibility. Interestingly, DA coating significantly increased the transfection efficiency of cationic PC，not due to the increase of cellular uptake, nor functioning as a receptor ligand, but was associated to the change of endocytosis pathway. Finally, using programmed cell death protein 4 (PDCD4) as a functional gene, DA coating PC NPs showed improved therapeutic effect and biocompatibility on tumor bearing mice. We believe that this DA coating PC NPs provides a facile method to improve the performance of cationic polymer vectors in gene therapy and has great potential for clinical applications.

Biocompatible fluorinated poly(ß-amino ester)s for safe and efficient gene therapy.

Cationic polymers have been widely used as one of the most promising non-viral vehicles for gene delivery due to their potential safety and ease of large-scale production. Here, we report the design and synthesis of a series of novel biodegradable fluorinated poly(ß-amino ester)s (FPBAEs) by simple Michael-addition reaction as safe and efficient gene carrier. The results of transfection efficacy assay demonstrated the optimal FPBAE could mediated much higher GFP expression than the commercial transfection agents, polyethyleneimine (PEI, Mw = 25K) and Lipo 2000, as well as the non-fluorinated poly(ß-amino ester)s (PBAE) on both HeLa and HEK-293T cell lines (higher than 70 and 90%, respectively), which was largely attributed to fluorination. Moreover, MTT and hemolysis assay indicated a preferable biocompatibility of FPBAE compared with PEI 25K owing to the low molecular weight and the presence of cleavable ester bonds. Taken together, the novel polymer FPBAE with both excellent gene transfection efficacy and much lower toxicity could serve as a desirable gene vector.

A novel design of a polynuclear co-delivery system for safe and efficient cancer therapy.

We report a novel and easy-to-fabricate polynuclear nanoparticle based on the collaborative re-assembly of nanoparticles as a robust chemogene co-delivery platform. Specifically, the polynuclear nanoparticle carrying DOX and siBcl-2 exerts remarkable co-delivery efficiency, increases tumour cell apoptosis and inhibits tumour cell proliferation in vitro and in vivo.

A new strategy for hydrophobic drug delivery using a hydrophilic polymer equipped with stacking units.

A highly hydrophilic polymer equipped with guanidinium groups was used to load aromatic ring-containing hydrophobic agent doxorubicin (DOX) via π-π interaction. The results have shown that the delivery system exhibited enhanced cellular uptake and antitumor efficiency compared with free drugs. This study opens new avenues for the application of hydrophilic polymers in drug delivery.

Regulating the Golgi apparatus by co-delivery of a COX-2 inhibitor and Brefeldin A for suppression of tumor metastasis.

Finding a cure for breast cancer currently remains a medical challenge in due to the failure of common treatment methods to inhibit invasion and metastasis of cancer cells, which eventually leads to recurrence of breast cancer. Many secreted proteins are overexpressed and play crucial roles in tumorigenesis and development. The Golgi apparatus is a key protein processing and secretion factory in which metastasis-associated proteins are modified, transported and secreted; thus, regulating the Golgi apparatus of tumor cells is a viable strategy to inhibit tumor metastasis. Herein, celecoxib (CLX) and Brefeldin A (BFA) were encapsulated into the biocompatible polymer PLGA-PEG to form nanoparticles that act on the Golgi apparatus to treat metastatic breast cancer; CLX is a specific COX-2 inhibitor which accumulates in the Golgi apparatus, and BFA is a protein transport inhibitor fusing the Golgi apparatus into endoplasmic reticulum. The optimized CLX and BFA co-loaded nanoparticles (CBNPs) possessed good physicochemical properties. CBNPs efficiently damaged the Golgi apparatus within 30 min and showed enhanced cytotoxicity of CLX and BFA toward murine metastatic breast cancer 4T1 cells. The migration and invasion abilities of the cells were dramatically suppressed by the CBNPs. Further, the expression and secretion of metastasis-associated proteins such as matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) were remarkably decreased. Our findings showed that co-delivering CLX and BFA to regulate the Golgi apparatus may be an efficient strategy to inhibit breast cancer growth and suppress tumor cell metastasis.

Vitamin A-decorated biocompatible micelles for chemogene therapy of liver fibrosis.

Liver fibrosis refers to excessive accumulation of hepatic collagen, which is primarily produced by activated hepatic stellate cells (HSCs). No effective drugs are clinically available to treat this condition, reflecting the fact that antifibrotic drugs do not specifically target activated HSCs. Here, we report the synthesis and evaluation of poly (lactide-co-glycolide)-polyspermine-poly (ethylene glycol)-vitamin A (PLGA-PSPE-PEG-VA), and activated HSC-targeted, biocompatible amphiphilic polymers for co-delivery of chemical (silibinin) and genetic (siCol1α1) drugs that synergistically suppress collagen I accumulation in fibrogenesis. PLGA-PSPE-PEG-VA self-assembled into core-shell polymeric micelles (PVMs) at low concentrations. After loading with silibinin and siCol1α1, the resulting chemical/genetic drug-loaded PVMs (CGPVMs) exhibited a small particle size and a slightly positive surface. CGPVMs had very low cytotoxicity and hemolytic activity in vitro and were well tolerated in mice, with no liver toxicity or inflammation. Importantly, CGPVMs effectively accumulated in fibrotic livers and specifically targeted activated HSCs. As expected CGPVMs more efficiently decreased collagen I production and ameliorated liver fibrosis compared with chemical drug (silibinin)-loaded PVMs (CPVMs) or genetic drug (siCol1α1)-loaded PVMs (GPVMs) only. These results indicate that CGPVMs are a promising tool for targeted delivery of chemogenes to activated HSCs in the treatment of liver fibrosis.

Curcumin-coordinated nanoparticles with improved stability for reactive oxygen species-responsive drug delivery in lung cancer therapy.

BACKGROUND: The natural compound curcumin (Cur) can regulate growth inhibition and apoptosis in various cancer cell lines, although its clinical applications are restricted by extreme water insolubility and instability. To overcome these hurdles, we fabricated a Cur-coordinated reactive oxygen species (ROS)-responsive nanoparticle using the interaction between boronic acid and Cur. MATERIALS AND METHODS: We synthesized a highly biocompatible 4-(hydroxymethyl) phenylboronic acid (HPBA)-modified poly(ethylene glycol) (PEG)-grafted poly(acrylic acid) polymer (PPH) and fabricated a Cur-coordinated ROS-responsive nanoparticle (denoted by PPHC) based on the interaction between boronic acid and Cur. The mean diameter of the Cur-coordinated PPHC nanoparticle was 163.8 nm and its zeta potential was -0.31 mV. The Cur-coordinated PPHC nanoparticle improved Cur stability in physiological environment and could timely release Cur in response to hydrogen peroxide (H2O2). PPHC nanoparticles demonstrated potent antiproliferative effect in vitro in A549 cancer cells. Furthermore, the viability of cells treated with PPHC nanoparticles was significantly increased in the presence of N-acetyl-cysteine (NAC), which blocks Cur release through ROS inhibition. Simultaneously, the ROS level measured in A549 cells after incubation with PPHC nanoparticles exhibited an obvious downregulation, which further proved that ROS depression indeed influenced the therapeutic effect of Cur in PPHC nanoparticles. Moreover, pretreatment with phosphate-buffered saline (PBS) significantly impaired the cytotoxic effect of Cur in A549 cells in vitro while causing less damage to the activity of Cur in PPHC nanoparticle. CONCLUSION: The Cur-coordinated nanoparticles developed in this study improved Cur stability, which could further release Cur in a ROS-dependent manner in cancer cells.

pH-Responsive de-PEGylated nanoparticles based on triphenylphosphine-quercetin self-assemblies for mitochondria-targeted cancer therapy.

We have developed mitochondria-targeted self-assembled nanoparticles (NPs) based on amphiphilic triphenylphosphine-quercetin (TPP-Que) conjugates, which were further modified by poly(ethylene glycol) via a pH-responsive coordination bond to form TQ-PEG NPs. And it is revealed that the TQ-PEG NPs were more effective therapeutic agents compared with Que in vitro and in vivo.

In vivo synergistic antitumor effect and safety of siRNA and lonidamine dual-loaded hierarchical targeted nanoparticles.

Based on development of nano-delivery system, co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) has exerted a promising advantage in cancer therapy. In this work, the superiority of synergistic therapy and safety of the hierarchical targeted co-delivery system loaded with siRNA and lonidamine (LND) were evaluated. The in vivo tumor accumulation ability and cancer growth inhibition effect of the polymer-blend nanocarriers were evaluated by a H22 subcutaneous sarcoma model. Moreover, hematoxylin and eosin (H&E) staining and transferase-mediated dUTP nick end-labeling (TUNEL) staining of tumor sections from each group were compared to assess the therapeutic efficacy. The dual-loaded nanocarriers had better tumor accumulation ability, remarkably inhibited growth of solid tumor in a synergistic manner, even significantly decreased hepatotoxicity of LND, and had good in vivo biocompatibility whereas LND alone showed serious hepatotoxicity. We believed that the dual-loaded hierarchical targeted delivery system with high effectiveness and biocompatibility would provide a promising approach for cancer combination therapy.

One-step assembly of polymeric demethylcantharate prodrug/Akt1 shRNA complexes for enhanced cancer therapy.

This report demonstrated a one-step assembly for co-delivering chemotherapeutics and therapeutic nucleic acids, constructed by integrating drug molecules into a nucleic acid condensing polymeric prodrug through degradable linkages. Demethylcantharate was selected as the model drug and pre-modified by esterifying its two carboxylic groups with 2-hydroxyethyl acrylate. The synthesized demethylcantharate diacrylate was then used to polymerize with linear polyethyleneimine (PEI 423) through a one-step Michael-addition reaction. The obtained cationic polymeric demethylcantharate prodrug was used to pack Akt1 shRNA into complexes through a one-step assembly. The formed complexes could release the parent drug demethylcantharate and Akt1 shRNA through the hydrolysis of ester bonds. Cellular assays involving cell uptake, cytotoxicity, and cell migration indicated that demethylcantharate and Akt1 shRNA co-delivered in the present form significantly and synergistically suppress the growth and metastasis of three human cancer cells. This work suggests that incorporating drug molecules into a nucleic acid-packing cationic polymer as a polymeric prodrug in a degradable form is a highly convenient and efficient way to co-deliver drugs and nucleic acids for cancer therapy.

Biocompatible polymeric nanocomplexes as an intracellular stimuli-sensitive prodrug for type-2 diabetes combination therapy.

Combination therapy is usually considered as a promising strategy owing to its advantages such as reduced doses, minimized side effects and improved therapeutic efficiency in a variety of diseases including diabetes. Here we synthesized a new highly intracellular stimuli-sensitive chitosan-graft-metformin (CS-MET) prodrug by imine reaction between oxidative chitosan and metformin for type 2 diabetes (T2D) therapy. Hypothetically, CS-MET functions dually as an anti-diabetes prodrug as well as a gene delivery vector without superfluous materials. CS-MET formed nanocomplexes with therapeutic gene through electrostatic interactions and entered cells by Organic Cation Transporter (OCT)-independent endocytosis. The incorporation of metformin into chitosan has been found to increase endosomal escape via the proton sponge effect. When vector carrying a short-hairpin RNA (shRNA) silencing sterol regulatory element-binding protein (SREBP), a major transcription factor involved in de novo lipogenisis, it reduced the SREBP mRNA and proteins efficiently. Furthermore, by intraperitoneal injection, CS-MET/shSREBP nanocomplexes effectively knocked down SREBP in livers of western-type diet (WD)-induced obese C57BL/6J mice, markedly reversed insulin resistance and alleviated the fatty liver phenotype without obvious toxic effects. Thus we were able to show that the intracellular stimuli-sensitive CS-MET prodrug renders a potential platform to increase the anti-diabetes activity with synergistic enhancement of gene therapy.