Homotypic SCOTIN assemblies form ER-endosome membrane contacts and regulate endosome dynamics.

The ER regulates the spatiotemporal organization of endolysosomal systems by membrane contact. In addition to tethering via heterotypic interactions on both organelles, we present a novel ER-endosome tethering mechanism mediated by homotypic interactions. The single-pass transmembrane protein SCOTIN is detected in the membrane of the ER and endosomes. In SCOTIN-knockout (KO) cells, the ER-late endosome contacts are reduced, and the perinuclear positioning of endosomes is disturbed. The cytosolic proline-rich domain (PRD) of SCOTIN forms homotypic assemblies in vitro and is necessary for ER-endosome membrane tethering in cells. A region of 28 amino acids spanning 150-177 within the SCOTIN PRD is essential to elicit membrane tethering and endosomal dynamics, as verified by reconstitution in SCOTIN-KO cells. The assembly of SCOTIN (PRD) is sufficient to mediate membrane tethering, as purified SCOTIN (PRD), but not SCOTIN (PRDΔ150-177), brings two different liposomes closer in vitro. Using organelle-specific targeting of a chimeric PRD domain shows that only the presence on both organellar membranes enables the ER-endosome membrane contact, indicating that the assembly of SCOTIN on heterologous membranes mediates organelle tethering.

Quadruple ultrasound, photoacoustic, optical coherence, and fluorescence fusion imaging with a transparent ultrasound transducer.

Ultrasound and optical imagers are used widely in a variety of biological and medical applications. In particular, multimodal implementations combining light and sound have been actively investigated to improve imaging quality. However, the integration of optical sensors with opaque ultrasound transducers suffers from low signal-to-noise ratios, high complexity, and bulky form factors, significantly limiting its applications. Here, we demonstrate a quadruple fusion imaging system using a spherically focused transparent ultrasound transducer that enables seamless integration of ultrasound imaging with photoacoustic imaging, optical coherence tomography, and fluorescence imaging. As a first application, we comprehensively monitored multiparametric responses to chemical and suture injuries in rats' eyes in vivo, such as corneal neovascularization, structural changes, cataracts, and inflammation. As a second application, we successfully performed multimodal imaging of tumors in vivo, visualizing melanomas without using labels and visualizing 4T1 mammary carcinomas using PEGylated gold nanorods. We strongly believe that the seamlessly integrated multimodal system can be used not only in ophthalmology and oncology but also in other healthcare applications with broad impact and interest.

Transcytosis-Inducing Multifunctional Albumin Nanomedicines with Deep Penetration Ability for Image-Guided Solid Tumor Treatment.

Transcytosis is an active transcellular transportation pathway that has garnered interest for overcoming the limited deep penetration of nanomedicines in solid tumors. In this study, a charge-convertible nanomedicine that facilitates deep penetration into solid tumors via transcytosis is designed. It is an albumin-based calcium phosphate nanomedicine loaded with IR820 (mAlb-820@CaP) for high-resolution photoacoustic imaging and enhanced photothermal therapy. Biomineralization on the surface stabilizes the albumin-IR820 complex during circulation and provides calcium ions (Ca2+ ) for tissue penetration on degradation in an acidic environment. pH-triggered transcytosis of the nanomedicine enabled by caveolae-mediated endocytosis and calcium ion-induced exocytosis in 2D cellular, 3D spheroid, and in vivo tumor models is demonstrated. Notably, the extravasation and penetration ability of the nanomedicine is observed in vivo using a high-resolution photoacoustic system, and nanomedicine shows the most potent photothermal antitumor effect in vivo. Overall, the strategy provides a versatile theragnosis platform for both noninvasive photoacoustic imaging and high therapeutic efficiency resulting from deep penetration of nanomedicine.

Nitric-Oxide-Modulatory Materials for Biomedical Applications.

Nitric oxide (NO) is an endogenous signaling molecule that participates in various physiological and biological pathways associated with vasodilation, immune response, and cell apoptosis. Interestingly, NO has versatile and distinct functions in vivo depending on its concentration and the duration of exposure; it aids cellular proliferation at nanomolar concentrations but causes cellular death at micromolar concentrations. Therefore, achieving the precise and on-demand modulation of microenvironmental NO concentrations has become a major research target in biomedical fields. To this end, many studies have investigated feasible means for developing functional moieties that can either exogenously donate or selectively scavenge NO. However, these advances are limited by poor stability and a lack of target specificity, which represent two significant obstacles regarding the spatiotemporal adjustment of NO in vivo. Our group has addressed this issue by contributing to the development of next-generation NO-modulatory materials over the past decade. Over this period, we utilized various polymeric, inorganic, and hybrid systems to enhance the bioavailability of traditional NO donors or scavengers in an attempt to maximize their clinical usage while also minimizing their unwanted side effects. In this Account, strategies regarding the rational design of NO-modulatory materials are first summarized and discussed, depending on their specific purposes. These strategies include chemical approaches for encapsulating traditional NO donors inside specific vehicles; this prevents spontaneous NO release and allows said donors to be exposed on-demand, under a certain stimulus. The current status of these approaches and the recent contributions of other groups are also comprehensively discussed here to ensure an objective understanding of the topic. Moreover, in this paper, we discuss strategies for the selective depletion of NO from local inflammatory sites, where the overproduction of NO is problematic. Finally, the major challenges for current NO-modulatory systems are discussed, and requirements are outlined that need to be tackled to achieve their future therapeutic development. Starting from this current, relatively early stage of development, we propose that, through continuous efforts to surmount existing challenges, it will be possible in the future to achieve clinical translations regarding NO-modulatory systems. This Account provides insightful guidelines regarding the rational design of NO-modulatory systems for various biomedical applications. Moreover, it can facilitate the achievement of previously unattainable goals while revolutionizing future therapeutics.

Effects of Resistance Exercise Program on Pain, Stress, Range of Motion, and Body Composition of Older Adults: A Randomized Controlled Trial.

Context: Aging is connected to a decline in muscular strength, flexibility, and agility. Some studies have found that resistance exercise using an elastic band can prevent chronic health problems such as osteoporosis, degenerative diseases, and frozen shoulders. Objective: The study intended to investigate the effects of a 12-week program of resistance exercise using an elastic band on the pain, stress, range of motion (ROM), and body composition of older adults. Design: The research team designed a randomized controlled trial (RCT). Setting: The study took place in Gimcheon City in the Republic of Korea. Participants: Participants were 80 adults aged 60 or older residing in the community. Intervention: Participants were randomly assigned using random number generation to an intervention group (n = 40) or a control group (n = 40). The intervention group participated in a resistance exercise program using an elastic band three days a week for 12 weeks. The control group followed a daily routine for 12 weeks. Outcome Measures: Measurements were conducted three times: at baseline, at the sixth week of treatment, and postinterventon. Results: Regarding participants' general characteristics and homogeneity of the dependent variables at baseline, no significant differences existed between the groups. Postintervention, 6 weeks a significant difference in stress (F = -4.02, P < .001) between the two groups. Moreover, significant variances in the shoulders' ROM (left, F = 3.40, P < .001; and right, F = 3.83, P < .001) a significant difference. 12 weeks a significant difference in shoulder pain existed (F = 19.58, P < .001), and stress (F = 15.36, P < .001) between the two groups. Moreover, significant variances in the shoulders' ROM (left, F = 4.63, P < .001; and right, F = 5.30, P < .001), as well as in the thickness of muscles (left, F = 5.55, P < .001; and right, F = 3.10, P = .003), between the two groups. As a result of measuring the right fat thickness, a significant difference in the target area was also found (left, F = -2.748, P = .008; and right, F = -3.13, P = .002). Conclusions: The resistance exercise that participants performed gradually reduced participants' shoulder pain and stress, improved their shoulders' ROM, and increased muscle mass around the shoulder joint. Therefore, the program can be recommended for adults aged 60 or older complaining of shoulder pain, to reduce shoulder pain and stress, improve joint ROM, and enhance body composition around the shoulder joint.

Surgical rectus sheath block combined with multimodal pain management reduces postoperative pain and analgesic requirement after single-incision laparoscopic appendectomy: a retrospective study.

PURPOSE: This study aimed to evaluate the impact of multimodal postoperative pain management, performing a surgical rectus sheath (RS) block via ropivacaine injection into the surgical field after single-incision laparoscopic appendectomy (SILA). METHODS: Patients who underwent single-incision laparoscopic appendectomy (SILA) for acute appendicitis were divided into three groups and compared: group 1 (multimodal pain management that included intraoperative application of a surgical RS block), group 2 (conventional pain management with intravenous opioids), or group 3 (multimodal pain management without RS block). Forty, 53, and 42 patients were registered, respectively (Table 1). RESULTS: Time to start a liquid (1.2 ± 0.4 h) in group 1 was statistically significantly shorter than that in group 2 (16.3 ± 8.4 h; p < 0.001) and group 3 (4.93 ± 2.3 h; p < 0.001). The median and max postoperative VAS scores in group 1 (1.6 ± 1.2 and 2.2 ± 1.8, respectively) were statistically significantly lower than that in group 2 (3.0 ± 1.2 and 4.2 ± 1.9, respectively; p < 0.001 on both accounts) and group 3 (2.9 ± 0.6 and 3.4 ± 1.2, respectively; p < 0.001 on both accounts). The postoperative hospital stay for group 1 (17.0 ± 9.4 h) was shorter than that for group 2 (44.7 ± 27.9 h; p < 0.001) and group 3 (35.4 ± 20.9 h; p < 0.001). RS block was a significant factor for reducing length of hospital stay and postoperative pain in 24 h. CONCLUSIONS: A surgical RS block combined with multimodal pain management after SILA is a safe and effective method that results in reduced postoperative pain and shorter hospitalization.

Phenylboronic acid conjugated to doxorubicin nanocomplexes as an anti-cancer drug delivery system in hepatocellular carcinoma.

Anti-cancer strategies using nanocarrier systems have been explored in a variety of cancers; these systems can easily be incorporated into tumors via the enhanced permeability and retention (EPR) effect leading to enhanced anti-tumor activity while reducing systemic toxicity by specific tumor-targeting. The prognosis of hepatocellular carcinoma (HCC) is extremely poor when the condition is diagnosed at the unresectable stage as treatment options are limited. In order to improve the treatment of cancer and the overall anti-cancer effect, polymerized phenylboronic acid conjugated doxorubicin (pPBA-Dox) nanocomplexes were generated, and conjugated doxorubicin, which is conventionally used in HCC. The nanocomplexes exhibited enhanced anti-tumor activity via tumor-specific targeting in the subcutaneous and orthotopic HCC syngeneic mice tumor model, implying that the nanocomplexes facilitate the targeted Dox delivery to liver cancer in which the sialic acid is over-expressed. Therefore, this study provides insight into the novel targeted therapy using the nanocomplexes for the treatment of HCC.

Effect of Atmospheric-Pressure Plasma Treatments on Fracture Toughness of Carbon Fibers-Reinforced Composites.

In this study, nano-scale fillers are added to epoxy matrix-based carbon fibers-reinforced composites (CFRPs) to improve the mechanical properties of multi-scale composites. Single-walled carbon nanotubes (SWCNTs) used as nano-scale fillers are treated with atmospheric-pressure plasma to introduce oxygen functional groups on the fillers' surface to increase the surface free energy and polar component, which relates to the mechanical properties of multi-scale composites. In addition, the effect of dispersibility was analyzed through the fracture surfaces of multi-scale composites containing atmospheric-pressure plasma-treated SWCNTs (P-SWCNTs) under high load conditions. The fillers content has an optimum weight percent load at 0.5 wt.% and the fracture toughness (KIC) method is used to demonstrate an improvement in mechanical properties. Here, KIC was calculated by three equations based on different models and we analyzed the correlation between mechanical properties and surface treatment. Compared to the composites of untreated SWCNTs, the KIC value is improved by 23.7%, suggesting improved mechanical properties by introducing selective functional groups through surface control technology to improve interfacial interactions within multi-scale composites.

Poly(cyclodextrin)-Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy.

Despite the approval of oncolytic virus therapy for advanced melanoma, its intrinsic limitations that include the risk of persistent viral infection and cost-intensive manufacturing motivate the development of analogous approaches that are free from the disadvantages of virus-based therapies. Herein, we report a nanoassembly comprised of multivalent host-guest interactions between polymerized paclitaxel (pPTX) and nitric oxide incorporated polymerized ß-cyclodextrin (pCD-pSNO) that through its bioactive components and when used locoregionally recapitulates the therapeutic effects of oncolytic virus. The resultant pPTX/pCD-pSNO exhibits significantly enhanced cytotoxicity, immunogenic cell death, dendritic cell activation and T cell expansion in vitro compared to free agents alone or in combination. In vivo, intratumoral administration of pPTX/pCD-pSNO results in activation and expansion of dendritic cells systemically, but with a corresponding expansion of myeloid-derived suppressor cells and suppression of CD8+ T cell expansion. When combined with antibody targeting cytotoxic T lymphocyte antigen-4 that blunts this molecule's signaling effects on T cells, intratumoral pPTX/pCD-pSNO treatment elicits potent anticancer effects that significantly prolong animal survival. This formulation thus leverages the chemo- and immunotherapeutic synergies of paclitaxel and nitric oxide and suggests the potential for virus-free nanoformulations to mimic the therapeutic action and benefits of oncolytic viruses.

Synthesis of Near-Infrared-Emitting Benzorhodamines and Their Applications to Bioimaging and Photothermal Therapy.

Photostable and near-infrared (NIR)-emitting organic fluorophores with large Stokes shifts are in great demand for long-term bioimaging at deeper depths with minimal autofluorescence and self-quenching. Herein, a new class of benzorhodamines and their analogues that are photostable and emit in the NIR region (up to 785 nm) with large Stokes shifts (>120 nm) is reported. The synthesis involves condensation of 7-alkylamino-2-naphthols with 2-[4-(dimethylamino)-2-hydroxybenzoyl]benzoic acid, which leads to bent-shaped benzorhodamines that emit orange fluorescence (≈600 nm); however, introduction of steric hindrance near the condensation site switched the regioselectivity, to provide a linear benzorhodamine system for the first time. The linear benzorhodamine derivatives provide bright fluorescence images in cells and in tissue. A carboxy-benzorhodamine was applied for photothermal therapy of cancer cells and xenograft cancer mice.

Drug-loaded titanium dioxide nanoparticle coated with tumor targeting polymer as a sonodynamic chemotherapeutic agent for anti-cancer therapy.

Sonodynamic therapy utilizes ultrasound (US)-responsive generation of reactive oxygen species (ROS) from sonosensitizer, and it is a powerful strategy for anti-cancer treatment in combination with chemotherapy. Herein, we report a precisely designed sonodynamic chemotherapeutics which exhibits US-responsive drug release via ROS generation from co-loaded sono-sensitizer. Doxorubicin (DOX)-coordinated titanium dioxide nanoparticles (TNPs) were encapsulated with polymeric phenyboronic acid (pPBA) via phenylboronic ester bond between pPBA and DOX. Loaded DOX was readily released under US irradiation due to the ROS-cleavable characteristics of phenylboronic ester bond. The size of nanoparticles was around 200 nm, and DOX was released by ROS generated under US irradiation. Tumor targeting by PBA moiety, intracellular ROS generation, and combined therapeutic effect against tumor cells were confirmed in vitro. Finally, we demonstrated high tumor accumulation and efficient tumor growth inhibition in tumor-bearing mice under US irradiation, which revealed potential as a multi-functional agent for sonodynamic chemotherapy.

Nitric Oxide-Scavenging Nanogel for Treating Rheumatoid Arthritis.

Nitric oxide (NO), a radical gas molecule produced by nitric oxide synthase, plays a key role in the human body. However, when endogenous NO is overproduced by physiological disorders, severe inflammatory diseases such as rheumatoid arthritis (RA) can occur. Therefore, scavenging NO may be an alternative strategy for treating inflammatory disorders. In our previous study, we developed a NO-responsive macrosized hydrogel by incorporating a NO-cleavable cross-linker (NOCCL); here, we further evaluate the effectiveness of the NO-scavenging nanosized hydrogel (NO-Scv gel) for treating RA. NO-Scv gel is simply prepared by solution polymerization between acrylamide and NOCCL. When the NO-Scv gel is exposed to NO, NOCCL is readily cleaved by consuming the NO molecule, as demonstrated in a Griess assay. As expected, the NO-Scv gel reduces inflammation levels by scavenging NO in vitro and shows excellent biocompatibility. Furthermore, the more promising therapeutic effect of the NO-Scv gel in suppressing the onset of RA is observed in vivo in a mouse RA model when compared to the effects of dexamethasone, a commercial drug. Therefore, our findings suggest the potential of the NO-Scv gel for biomedical applications and further clinical translation.

Supramolecular Phthalocyanine Assemblies for Improved Photoacoustic Imaging and Photothermal Therapy.

Phototheranostic nanoplatforms are of particular interest for cancer diagnosis and imaging-guided therapy. Herein, we develop a supramolecular approach to fabricate a nanostructured phototheranostic agent through the direct self-assembly of two water-soluble phthalocyanine derivatives, PcS4 and PcN4. The nature of the molecular recognition between PcS4 and PcN4 facilitates the formation of nanostructure (PcS4-PcN4) and consequently enables the fabrication of PcS4-PcN4 with completely quenched fluorescence and reduced singlet oxygen generation, leading to the high photoacoustic and photothermal activity of PcS4-PcN4. In vivo evaluations suggest that PcS4-PcN4 could not only efficiently visualize a tumor with high contrast through whole-body photoacoustic imaging but also enable excellent photothermal therapy for cancer.

Synthesis and Characterization of Nitric Oxide-Releasing Platinum(IV) Prodrug and Polymeric Micelle Triggered by Light.

Herein, we report the proof of concept of photoresponsive chemotherapeutics comprising nitric oxide-releasing platinum prodrugs and polymeric micelles. Photoactivatable nitric oxide-releasing donors were integrated into the axial positions of a platinum(IV) prodrug, and the photolabile hydrophobic groups were grafted in the block copolymers. The hydrophobic interaction between nitric oxide donors and the photolabile groups allowed for the loading of platinum drugs and nitric oxide-releasing donors in the photolabile polymeric micelles. After cellular uptake of micelles, light irradiation induced the release of nitric oxide, which sensitized the cancer cells. Simultaneously, photolabile hydrophobic groups were cleaved from micelles, and the nitric oxide-releasing donor was altered to be more hydrophilic, resulting in the rapid release of platinum(IV) prodrugs. The strategy of using platinum(IV) prodrugs and nitric oxide led to enhanced anticancer effects.

Miktoarm Amphiphilic Block Copolymer with Singlet Oxygen-Labile Stereospecific ß-Aminoacrylate Junction: Synthesis, Self-Assembly, and Photodynamically Triggered Drug Release.

Incorporation of a desired stimuli-responsive unit in a stereospecific manner at the specific location within a nonlinear block copolymer architecture is a challenging task in synthetic polymer chemistry. Herein, we report a facile and versatile method to synthesize AB2 miktoarm block copolymers bearing a singlet oxygen (1O2)-labile regio and stereospecific ß-aminoacrylate linkage with 100% E-configuration at the junction via a combination of amino-yne click chemistry and ring opening polymerization. Using this strategy, a series of 1O2-responsive AB2 amphiphilic miktoarm (MA) copolymers composed of hydrophilic polyethylene glycol (PEG) as the A constituent and hydrophobic polycaprolactone (PCL) as the B constituent (MA-PEG- b-PCL2) was synthesized by varying the block length of PCL. The self-assembly characteristics of these well-defined MA-PEG- b-PCL2 copolymers in an aqueous condition were studied by solvent displacement and thin-film hydration method, and their morphologies were investigated using transmission electron microscopy. The copolymers formed spherical, cylindrical, or lamella morphologies, depending on the chain length and preparation conditions. A hydrophobic photosensitizer chlorin e6 (Ce6) and anticancer drug doxorubicin (DOX) were efficiently encapsulated into the hydrophobic core of MA-PEG- b-PCL2 copolymer micelles. These coloaded micelles were taken up by human breast cancer (MDA-MB-231) cells. Upon red laser light irradiation, the 1O2-generated by the Ce6 induced photocleavage of the ß-aminoacrylate moiety, leading to the dissociation of the micellar structure and triggered intracellular drug release for effective therapy. Overall, rapid disassembly upon 1O2 generation and subsequent controlled intracellular drug release suggested that these micelles bearing ß-aminoacrylate linkage have a huge potential for on-demand drug delivery.

Effective PEI-mediated delivery of CRISPR-Cas9 complex for targeted gene therapy.

The-state-of-art CRISPR/Cas9 is one of the most powerful among the approaches being developed to rescue fundamental causes of gene-based inheritable diseases. Several strategies for delivering such genome editing materials have been developed, but the safety, efficacy over time, cost of production, and gene size limitations are still under debate and must be addressed to further improve applications. In this study, we evaluated branched forms of the polyethylenimine (PEI) - branched PEI 25 kDa (BPEI-25K) - and found that it could efficiently deliver CRISPR/Cas9 plasmids. Plasmid DNA expressing both guide RNA and Cas9 to target the Slc26a4 locus was successfully delivered into Neuro2a cells and meditated genome editing within the targeted locus. Our results demonstrated that BPEI-25K is a promising non-viral vector to deliver the CRISPR/Cas9 system in vitro to mediate targeted gene therapy, and these findings contribute to an understanding of CRISPR/Cas9 delivery that may enable development of successful in vivo techniques.

Self-Assembled Nanoconstructs Modified with Amplified Aptamers Inhibited Tumor Growth and Retinal Vascular Hyperpermeability via Vascular Endothelial Growth Factor Capturing.

Here, nanoconstructs consisting of a DNA-amplified aptamer with a biocompatible polymer backbone for capturing target biomolecules are presented. First, the polymer-DNA nanoconstructs were prepared by hybridization of two complementary single-stranded DNAs that were each conjugated to a dextran polymer backbone. The designed polymer-DNA amplified aptamer nanoconstructs (PA-aNCs) were then prepared by utilizing polymer-DNA nanoconstructs conjugated with an aptamer (PA-NCs) using a rolling circle amplification reaction to amplify the aptamer. These PA-aNCs were successfully applied to alleviate tumor growth and vascular endothelial growth factor (VEGF)-induced retinal vascular hyperpermeability in vivo through the highly effective capture of human VEGF as a target molecule. These PA-aNCs could be used as therapeutic agent for anti-VEGF therapy by efficiently capturing human VEGF.

Self-assembled nanocomplex between polymerized phenylboronic acid and doxorubicin for efficient tumor-targeted chemotherapy.

Since the discovery that nano-scaled particulates can easily be incorporated into tumors via the enhanced permeability and retention (EPR) effect, such nanostructures have been exploited as therapeutic small molecule delivery systems. However, the convoluted synthetic process of conventional nanostructures has impeded their feasibility and reproducibility in clinical applications. Herein, we report an easily prepared formulation of self-assembled nanostructures for systemic delivery of the anti-cancer drug doxorubicin (DOX). Phenylboronic acid (PBA) was grafted onto the polymeric backbone of poly(maleic anhydride). pPBA-DOX nanocomplexes were prepared by simple mixing, on the basis of the strong interaction between the 1,3-diol of DOX and the PBA moiety on pPBA. Three nanocomplexes (1, 2, 4) were designed on the basis of [PBA]:[DOX] molar ratios of 1:1, 2:1, and 4:1, respectively, to investigate the function of the residual PBA moiety as a targeting ligand. An acid-labile drug release profile was observed, owing to the intrinsic properties of the phenylboronic ester. Moreover, the tumor-targeting ability of the nanocomplexes was demonstrated, both in vitro by confocal microscopy and in vivo by fluorescence imaging, to be driven by an inherent property of the residual PBA. Ligand competition assays with free PBA pre-treatment demonstrated the targeting effect of the residual PBA from the nanocomplexes 2 and 4. Finally, the nanocomplexes 2 and 4, compared with the free DOX, exhibited significantly greater anti-cancer effects in vitro and even in vivo. Our pPBA-DOX nanocomplex enables a new paradigm for self-assembled nanostructures with potential biomedical applications.

Single-Layered MoS2-PEI-PEG Nanocomposite-Mediated Gene Delivery Controlled by Photo and Redox Stimuli.

Stimuli-responsive gene delivery systems maximize therapeutic efficacy by controlling the cytosolic conveyance and rate of effective gene release. We present herein a hybrid nanocomposite composed of a 2D nanomaterial, MoS2, modified by attaching two polymers (polyethylenimine (PEI) and polyethylenglycol (PEG)) via disulfide bonds. This MoS2-PEI-PEG nanocomposite interacts with DNA by electrostatic interaction, and accordingly forms a nanosized complex with high stability. Photothermal conversion of MoS2 nanosheet is employed in order to induce photothermally triggered endosomal escape upon the near infrared light irradiation. After endosomal escape, polymers are detached from the MoS2 nanosheet by the intracellular reducing agent, glutathione (GSH), resulting in effective gene release from the nanocomposite. This sequential process initiated by external and internal stimuli remarkably enhances gene delivery efficiency by effective endosomal escape and gene release without severe cytotoxicity. Our rationally designed MoS2 nanocomposite provides a spatiotemporally controllable platform to deliver genetic material into cells.

Coordinative Amphiphiles as Tunable siRNA Transporters.

In this study, we developed coordinative amphiphiles for use as novel siRNA transporters. As a modification of a conventional cationic lipid structure, we replaced the cationic head with zinc(II)-dipicolylamine complex (Zn/DPA) as a phosphate-directing group, and used various membrane-directing groups in the place of the hydrophobic tails. These simple amphiphiles are readily synthesized and easy to modify. The Zn/DPA head groups bind to the phosphate backbones of siRNAs, and to our surprise, they prevented the enzymatic degradation of siRNAs by RNase A. Interestingly, the Zn/DPA head itself exhibited moderate transfection efficiency, and its combination with a membrane-directing group-oleoyl (CA1), pyrenebutyryl (CA2), or biotin (CA3)-enhanced the delivery efficiency without imparting significant cytotoxicity. Notably, the uptake pathway was tunable depending on the nature of the membrane-directing group. CA1 delivered siRNAs mainly through caveolae-mediated endocytosis, and CA2 through clathrin- and caveolin-independent endocytosis; CA3 recruited siRNAs specifically into biotin receptor-positive HepG2 cells through receptor-mediated endocytosis. Thus, it appears possible to develop tunable siRNA transporters simply by changing the membrane-directing parts. These are the first examples of amphiphilic siRNA transporters accompanying coordinative interactions between the amphiphiles and siRNAs.