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Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects. [ABSTRACT FROM AUTHOR]

The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives. [ABSTRACT FROM AUTHOR]

In this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)2k-b-poly(furfuryl methacrylate)1.5k (PEO2k-b-PFMA1.5k), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO2k-b-PFMA1.5k from FMA monomers and PEO2k-Br initiators. An anti-cancer drug, doxorubicin (DOX), was incorporated into PFMA hydrophobic parts of the polymeric micelles, which were then cross-linked with maleimide cross-linkers, 1,6-bis(maleimide) hexane, dithiobis(maleimido) ethane and diselenobis(maleimido) ethane via Diels–Alder reaction. Under physiological conditions, the structural stability of both S–S and Se–Se CCL micelles was maintained; however, treatments with 10 mM GSH induced redox-responsive de-cross-linking of S–S and Se–Se bonds. In contrast, the S–S bond was intact in the presence of 100 mM H2O2, while the Se–Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO2k-b-PFMA1.5k-Se)2 micelles varied more significantly in response to changes in the redox environment than (PEO2k-b-PFMA1.5k-S)2 micelles. In vitro release studies showed that the developed micelles had a lower drug release rate at pH 7.4, whereas a higher release was observed at pH 5.0 (tumor environment). The micelles were non-toxic against HEK-293 normal cells, which revealed that they could be safe for use. Nevertheless, DOX-loaded S–S/Se–Se CCL micelles exhibited potent cytotoxicity against BT-20 cancer cells. Based on these results, the (PEO2k-b-PFMA1.5k-Se)2 micelles can be more sensitive drug carriers than (PEO2k-b-PFMA1.5k-S)2 micelles. [ABSTRACT FROM AUTHOR]

The development of stimuli-responsive controlled release formulations is a potential method of improving pesticide utilization efficiency and alleviating current pesticide-related environmental pollution. In this study, a self-destruction redox-responsive pesticide delivery system using biodegradable disulfide-bond-bridged mesoporous organosilica (DMON) nanoparticles as the porous carriers and coordination complexes of gallic acid (GA) and Fe(III) ions as the capping agents were established for controlling prochloraz (PRO) release. The GA–Fe(III) complexes deposited onto the surface of DMON nanoparticles could effectively improve the light stability of prochloraz. Due to the decomposition of GA–Fe(III) complexes, the nano-vehicles had excellent redox-responsive performance under the reducing environments generated by the fungus. The spreadability of PRO@DMON–GA–Fe(III) nanoparticles on the rice leaves was increased due to the hydrogen bonds between GA and rice leaves. Compared with prochloraz emulsifiable concentrate, PRO@DMON–GA–Fe(III) nanoparticles showed better fungicidal activity against Magnaporthe oryzae with a longer duration under the same concentration of prochloraz. More importantly, DMON–GA–Fe(III) nanocarriers did not observe obvious toxicity to the growth of rice seedlings. Considering non-toxic organic solvents and excellent antifungal activity, redox-responsive pesticide controlled release systems with self-destruction properties have great application prospects in the field of plant disease management. [ABSTRACT FROM AUTHOR]

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells. [ABSTRACT FROM AUTHOR]

Endo/lysosomal escape and subsequent nuclear translocation are recognized as the two major challenges for efficient gene transfection. Herein, nuclear localization signal (NLS) peptide sequences and oligomeric lysine sequences were crosslinked via disulfide bonds to obtain glutathione (GSH) reducible polypeptide (pNLS). The pNLS could condense DNA into compact positive-charged complexes with redox sensitivity, and then gold nanoclusters (AuNC) were further decorated to the surface via electrostatic interactions obtaining versatile pNLS/DNA/AuNC complexes. The AuNC could generate reactive oxygen species (ROS) under NIR-irradiation and accelerate the endo/lysosomal escape of the complexes, and then the pNLS sequence degraded by GSH in cytoplasm would release the DNA and facilitate the subsequent nuclear translocation for enhanced gene transfection. [ABSTRACT FROM AUTHOR]

Stimuli-responsive hydrogels have a wide range of potential applications in microfluidics, which has drawn great attention. Double cross-linked hydrogels are very well suited for this application as they offer both stability and the required responsive behavior. Here, we report the integration of poly(N-isopropylacrylamide) (PNiPAAm) hydrogel with a permanent cross-linker (N,N′-methylenebisacrylamide, BIS) and a redox responsive reversible cross-linker (N,N′-bis(acryloyl)cystamine, BAC) into a microfluidic device through photopolymerization. Cleavage and re-formation of disulfide bonds introduced by BAC changed the cross-linking densities of the hydrogel dots, making them swell or shrink. Rheological measurements allowed for selecting hydrogels that withstand long-term shear forces present in microfluidic devices under continuous flow. Once implemented, the thiol-disulfide exchange allowed the hydrogel dots to successfully capture and release the protein bovine serum albumin (BSA). BSA was labeled with rhodamine B and functionalized with 2-(2-pyridyldithio)-ethylamine (PDA) to introduce disulfide bonds. The reversible capture and release of the protein reached an efficiency of 83.6% in release rate and could be repeated over 3 cycles within the microfluidic device. These results demonstrate that our redox-responsive hydrogel dots enable the dynamic capture and release of various different functionalized (macro)molecules (e.g., proteins and drugs) and have a great potential to be integrated into a lab-on-a-chip device for detection and/or delivery. [ABSTRACT FROM AUTHOR]

Mesoporous silica nanoparticles have been widely applied as carriers for cancer treatment. Among the different types of stimuli-responsive drug delivery systems, those sensitive to redox stimuli have attracted much attention. Their relevance arises from the high concentration of reductive species that are found within the cells, compared to bloodstream, which leads to the drug release taking place only inside cells. This review is intended to provide a comprehensive overview of the most recent trends in the design of redox-responsive mesoporous silica nanoparticles. First, a general description of the biological rationale of this stimulus is presented. Then, the different types of gatekeepers that are able to open the pore entrances only upon application of reductive conditions will be introduced. In this sense, we will distinguish among those targeted and those non-targeted toward cancer cells. Finally, a new family of bridged silica nanoparticles able to degrade their structure upon application of this type of stimulus will be presented. [ABSTRACT FROM AUTHOR]

Since urinary tract infections (UTIs) are closely associated with oxidative stress, we developed ROS-sensitive nanoparticles for ciprofloxacin (CIP) delivery for inhibition of UTI. Poly(D,L-lactide-co-glycolide) (PLGA)- selenocystamine (PLGA-selenocystamine) conjugates were attached to methoxypoly(ethylene glycol) (PEG) tetraacid (TA) (TA-PEG) conjugates to produce a copolymer (abbreviated as LGseseTAPEG). Selenocystamine linkages were introduced between PLGA and TA to endow reactive oxygen species (ROS) sensitivity to nanoparticles. CIP-incorporated nanoparticles of LGseseTAPEG copolymer were fabricated by W/O/W/W emulsion method. CIP-incorporated nanoparticles responded to H2O2 and then their morphologies were disintegrated by incubation with H2O2. Furthermore, particle size distribution of nanoparticles was changed from mono-modal distribution pattern to multi-modal distribution pattern by addition of H2O2. CIP release from nanoparticles of LGseseTAPEG copolymer was faster in the presence of H2O2 than in the absence of it. In antibacterial study using Escherichia coli (E. coli), free CIP and free CIP plus empty nanoparticles showed dose-dependent inhibitory effect against growth of bacteria while CIP-incorporated nanoparticles have less antibacterial activity compared to free CIP. These results were due to that CIP-incorporated nanoparticles have sustained release properties. When free CIP or CIP-incorporated nanoparticles were introduced into dialysis membrane to mimic in vivo situation, CIP-incorporated nanoparticles showed superior antibacterial activity compared to free CIP. At cell viability assay, nanoparticles of LGseseTAPEG copolymer have no acute cytotoxicity against L929 mouse fibroblast cells and CCD986sk human skin fibroblast cells. We suggest LGseseTAPEG nanoparticles are a promising candidate for CIP delivery. [ABSTRACT FROM AUTHOR]

Properties and applications of synthetic thiol- and disulfide-based materials, principally polymers, are reviewed. Emphasis is placed on soft and self-assembling materials in which interconversion of the thiol and disulfide groups initiates stimulus-responses and/or self-healing for biomedical and non-biomedical applications. [ABSTRACT FROM AUTHOR]

Drug targeting of tumor cells is one of the great challenges in cancer therapy; nanoparticles based on natural polymers represent valuable tools to achieve this aim. The ability to respond to environmental signals from the pathological site (e.g., altered redox potential), together with the specific interaction with membrane receptors overexpressed on cancer cells membrane (e.g., CD44 receptors), represent the main features of actively targeted nanoparticles. In this work, redox-responsive micelle-like nanoparticles were prepared by self-assembling of a hyaluronic acid–human serum albumin conjugate containing cystamine moieties acting as a functional spacer. The conjugation procedure consisted of a reductive amination step of hyaluronic acid followed by condensation with albumin. After self-assembling, nanoparticles with a mean size of 70 nm and able to be destabilized in reducing media were obtained. Doxorubicin-loaded nanoparticles modulated drug release rate in response to different redox conditions. Finally, the viability and uptake experiments on healthy (BALB-3T3) and metastatic cancer (MDA-MB-231) cells proved the potential applicability of the proposed system as a drug vector in cancer therapy. [ABSTRACT FROM AUTHOR]

"Smart" polymeric microcapsules with excellent permeability of membranes have drawn considerable attention in scientific and industrial research such as drug delivery carriers, microreactors, and artificial organelles. In this work, hybrid hollow polymeric microcapsules (HPs) containing redox-active gold-sulfide bond were prepared with bovine serum albumin, inorganic metal cluster (AuNCs), and poly(N-isopropylacrylamide) conjugates by using Pickering emulsion method. HPs were transferred from water-in-oil to water-in-water by adding PEGbis(N-succinimidylsuccinate). To achieve redox-responsive membrane, the Au-S bond units incorporated into the microcapsules' membranes, allowed us to explore the effects of a new stimuli, that is, the redox Au-S bond breaking on the microcapsules' membranes. The permeability of these hybrid hollow polymeric microcapsules could be sensitively tuned via adding environment-friendly hydrogen peroxide (H2O2), resulting from a fast fracture of Au-S bond. Meanwhile, AuNCs and conjugates could depart from the microcapsules, and enhance the permeability of the membrane. Based on the excellent permeability of the membrane, phosphatase was encapsuled into HPs and p-nitrophenyl phosphate as a substrate. After adding 1 × 10−2 and 1 × 10−4 M H2O2, the catalytic efficiency was nearly 4.06 and 2.22 times higher than that of HPs in the absence of H2O2, respectively. Hence, the unique redox-responsive HPs have potential applications in biocatalytic reaction, drug delivery, and materials as well as in bioscience. [ABSTRACT FROM AUTHOR]

Smart or stimuli-responsive materials are an emerging class of materials used for tissue engineering and drug delivery. A variety of stimuli (including temperature, pH, redox-state, light, and magnet fields) are being investigated for their potential to change a material's properties, interactions, structure, and/or dimensions. The specificity of stimuli response, and ability to respond to endogenous cues inherently present in living systems provide possibilities to develop novel tissue engineering and drug delivery strategies (for example materials composed of stimuli responsive polymers that self-assemble or undergo phase transitions or morphology transformations). Herein, smart materials as controlled drug release vehicles for tissue engineering are described, highlighting their potential for the delivery of precise quantities of drugs at specific locations and times promoting the controlled repair or remodeling of tissues. [ABSTRACT FROM AUTHOR]

Polymeric micelles (PMs) have been used to improve the poor aqueous solubility, slow absorption and non-selective biodistribution of chemotherapeutic agents (CAs), albeit, they suffer from disassembly and premature release of payloads in the bloodstream. To alleviate the thermodynamic instability of PMs, different core crosslinking approaches were employed. Herein, we synthesized the poly(ethylene oxide)-b-poly((2-aminoethyl)diselanyl)ethyl l-aspartamide)-b-polycaprolactone (mPEG-P(LA-DSeDEA)-PCL) copolymer which self-assembled into monodispersed nanoscale, 156.57 ± 4.42 nm, core crosslinked micelles (CCMs) through visible light-induced diselenide metathesis reaction between the pendant selenocystamine moieties. The CCMs demonstrated desirable doxorubicin (DOX)-loading content (7.31%) and encapsulation efficiency (42.73%). Both blank and DOX-loaded CCMs (DOX@CCMs) established appreciable colloidal stability in the presence of bovine serum albumin (BSA). The DOX@CCMs showed redox-responsive drug releasing behavior when treated with 5 and 10 mM reduced glutathione (GSH) and 0.1% H2O2. Unlike the DOX-loaded non-crosslinked micelles (DOX@NCMs) which exhibited initial burst release, DOX@CCMs demonstrated a sustained release profile in vitro where 71.7% of the encapsulated DOX was released within 72 h. In addition, the in vitro fluorescent microscope images and flow cytometry analysis confirmed the efficient cellular internalization of DOX@CCMs. The in vitro cytotoxicity test on HaCaT, MDCK, and HeLa cell lines reiterated the cytocompatibility (≥82% cell viability) of the mPEG-P(LA-DSeDEA)-PCL copolymer and DOX@CCMs selectively inhibit the viabilities of 48.85% of HeLa cells as compared to 15.75% of HaCaT and 7.85% of MDCK cells at a maximum dose of 10 µg/mL. Overall, all these appealing attributes make CCMs desirable as nanocarriers for the delivery and controlled release of DOX in tumor cells. [ABSTRACT FROM AUTHOR]

Dopamine-modified hyaluronic acid (HA-DOP) was chosen as the drug carrier in this study, and Cu2+ was selected from among Cu2+, Zn2+, Fe2+, and Ca2+ as the central atom. 6-Mercaptopurine (6-MP) was conjugated with HA through a coordination reaction. HA-DOP-copper-MP (HA-DOP-Cu-MP), a redox-responsive coordination polymer prodrug, was prepared. The drug loading was 49.5 mg/g, the encapsulation efficiency was 70.18%, and the particle size was 173.5 nm. HA-DOP-Cu-MP released rapidly in the release medium containing reduced glutathione (GSH), and the accumulated release exceeded 94% in 2 h. In the release medium without GSH, the drug release rate was slow, with only 15% of the 6-MP released in 24 h. Cell uptake experiments revealed the CD44 targeting of HA. Cell viability assays showed that the cytotoxicity of HA-DOP-Cu-MP was higher than that of free 6-MP. Indeed, HA-DOP-Cu-MP is very toxic to cancer cells. In this paper, the redox-responsive drug delivery system was synthesized by a coordination reaction. The tumour targeting and tumour cytotoxicity of 6-MP were improved. [ABSTRACT FROM AUTHOR]

In this study, a redox-sensitive chitosan derivative with modifications by cholesterol, sulfhydryl, and mPEG (mPEG-CS(SH)-CHO) was successfully synthesized and characterized. Due to its amphiphilicity, the conjugate could spontaneously form micelles in an aqueous environment. The optimized paclitaxel (PTX)-loaded mPEG-CS(SH)-CHO micelles, with a mean diameter of 158 nm, zeta potential of +26.9 mV, drug loading of 11.7%, and entrapment efficiency of 88.3%, were successfully prepared. The results of an XRD study demonstrated that PTX was loaded in the core of the micelles in a non-crystalline state. Inspiringly, the PTX-loaded micelles possessed excellent anticancer effect but low toxicity to the body. It can be concluded that the mPEG-CS(SH)-CHO micellar system is a promising drug delivery carrier for the controlled release of PTX. [ABSTRACT FROM AUTHOR]

The clinical efficacy of methotrexate (MTX) is limited by its poor water solubility, its low bioavailability, and the development of resistance in cancer cells. Herein, we developed novel folate redox-responsive chitosan (FTC) nanoparticles for intracellular MTX delivery. l-Cysteine and folic acid molecules were selected to be covalently linked to chitosan in order to confer it redox responsiveness and active targeting of folate receptors (FRs). NPs based on these novel polymers could possess tumor specificity and a controlled drug release due to the overexpression of FRs and high concentration of reductive agents in the microenvironment of cancer cells. Nanoparticles (NPs) were prepared using an ionotropic gelation technique and characterized in terms of size, morphology, and loading capacity. In vitro drug release profiles exhibited a glutathione (GSH) dependence. In the normal physiological environment, NPs maintained good stability, whereas, in a reducing environment similar to tumor cells, the encapsulated MTX was promptly released. The anticancer activity of MTX-loaded FTC-NPs was also studied by incubating HeLa cells with formulations for various time and concentration intervals. A significant reduction in viability was observed in a dose- and time-dependent manner. In particular, FTC-NPs showed a better inhibition effect on HeLa cancer cell proliferation compared to non-target chitosan-based NPs used as control. The selective cellular uptake of FTC-NPs via FRs was evaluated and confirmed by fluorescence microscopy. Overall, the designed NPs provide an attractive strategy and potential platform for efficient intracellular anticancer drug delivery. [ABSTRACT FROM AUTHOR]

Herein, we describe the fabrication and characterization of carbonized disulfide core-crosslinked polymer dots with pH-cleavable colorimetric nanosensors, based on diol dye-conjugated fluorescent polymer dots (L-PD), for reduction-triggered paclitaxel (PTX) release during fluorescence imaging-guided chemotherapy of tumors. L-PD were loaded with PTX (PTX loaded L-PD), via π–π stackings or hydrophobic interactions, for selective theragnosis by enhanced release of PTX after the cleavage of disulfide bonds by high concentration of glutathione (GSH) in a tumor. The nano-hybrid system showed fluorescence quenching behavior with less than 2% of PTX released under physiological conditions. However, in a tumor microenvironment, the fluorescence recovered at an acidic-pH, and PTX (approximately 100% of the drug release) was released efficiently out of the matrix by reduction caused by the GSH level in the tumor cells, which improved the effectiveness of the cancer treatment. Therefore, the colorimetric nanosensor showed promising potential in distinguishing between normal and cancerous tissues depending on the surrounding pH and GSH concentrations so that PTX can be selectively delivered into cancer cells for improved cancer diagnosis and chemotherapy. [ABSTRACT FROM AUTHOR]

The clinical efficacy of methotrexate (MTX) is limited by its poor water solubility, its low bioavailability, and the development of resistance in cancer cells. Herein, we developed novel folate redox-responsive chitosan (FTC) nanoparticles for intracellular MTX delivery. l-Cysteine and folic acid molecules were selected to be covalently linked to chitosan in order to confer it redox responsiveness and active targeting of folate receptors (FRs). NPs based on these novel polymers could possess tumor specificity and a controlled drug release due to the overexpression of FRs and high concentration of reductive agents in the microenvironment of cancer cells. Nanoparticles (NPs) were prepared using an ionotropic gelation technique and characterized in terms of size, morphology, and loading capacity. In vitro drug release profiles exhibited a glutathione (GSH) dependence. In the normal physiological environment, NPs maintained good stability, whereas, in a reducing environment similar to tumor cells, the encapsulated MTX was promptly released. The anticancer activity of MTX-loaded FTC-NPs was also studied by incubating HeLa cells with formulations for various time and concentration intervals. A significant reduction in viability was observed in a dose- and time-dependent manner. In particular, FTC-NPs showed a better inhibition effect on HeLa cancer cell proliferation compared to non-target chitosan-based NPs used as control. The selective cellular uptake of FTC-NPs via FRs was evaluated and confirmed by fluorescence microscopy. Overall, the designed NPs provide an attractive strategy and potential platform for efficient intracellular anticancer drug delivery.

Endo/lysosomal escape and subsequent nuclear translocation are recognized as the two major challenges for efficient gene transfection. Herein, nuclear localization signal (NLS) peptide sequences and oligomeric lysine sequences were crosslinked via disulfide bonds to obtain glutathione (GSH) reducible polypeptide (pNLS). The pNLS could condense DNA into compact positive-charged complexes with redox sensitivity, and then gold nanoclusters (AuNC) were further decorated to the surface via electrostatic interactions obtaining versatile pNLS/DNA/AuNC complexes. The AuNC could generate reactive oxygen species (ROS) under NIR-irradiation and accelerate the endo/lysosomal escape of the complexes, and then the pNLS sequence degraded by GSH in cytoplasm would release the DNA and facilitate the subsequent nuclear translocation for enhanced gene transfection.