Charge-converting nanocarriers: Phosphorylated polysaccharide coatings for overcoming intestinal barriers.

For the design of charge-converting nanocarriers (NCs), cationic lipid-based NCs containing curcumin as model drug were coated with phosphorylated starch (NC-SP) and phosphorylated dextran (NC-DP). NCs showed a drug encapsulation efficiency of 94 % and had a mean size of 175 to 180 nm. The recorded zeta potential of the core NC (cNC) was +8.3 mV, whereas it reversed to -10.6 mV and -7.4 mV after decorating with SP and DP, respectively. Furthermore, a 3-fold higher amount of curcumin having been incorporated in these NCs remained stable within 2 h of UV exposure indicating a photoprotective effect of this delivery system. Charge-converting properties were confirmed by cleavage with intestinal alkaline phosphatase (IAP) and resulted in a zeta potential shift of Δ15.4 mV for NC-SP and Δ11.2 mV for NC-DP. NC-SP and NC-DP showed enhanced mucus permeating properties compared to cNC, that were additionally confirmed by an up to 2.2-fold improved cellular uptake on mucus secreting Caco-2/HT29-MTX cells. According to these results, NC-SP and NC-DP coatings hold promise as a viable and efficient strategy for charge-converting NCs.

Intelligent Hydrogel with Physiologically Dependent Capacities of Photothermal Conversion and Nanocatalytic Medicine to Integratively Inhibit Bacteria and Inflammation for On-Demand Treatment of Infected Wound.

Although chemodynamic therapy (CDT) and photothermal therapy (PTT) based on a variety of nanoparticles have been developed to achieve effective anti-bacterial therapy, the limited therapeutic efficiency of CDT alone, as well as the undifferentiated damage of PTT to both bacteria and surrounding healthy tissue are still challenges for their clinical application of infected wounds treatments. In addition, during the CDT and PTT-mediated antimicrobial processes, the endogenous macrophages would be easily converted to pro-inflammatory macrophages (M1 phenotype) under local ROS and hyperthermia to promote inflammation, resulting in unexpected suppression of tissue regeneration and possible wound deterioration. To address these problems, a biodegradable sodium alginate/hyaluronic acid hydrogel loaded with functional CeO2-Au nano-alloy (AO@ACP) is fabricated to not only achieve precise and efficient antibacterial activity through infection-environment dependent photothermal-chemodynamic therapy but also rapidly eliminate the excess reactive oxygens (ROS) in the M1 type macrophage at the infected area to induce their polarization to M2 type for significant inhibition of inflammation and remarkable enhancement of tissue regeneration, hopefully developing an effective strategy to treat infected wound.

Charge-Reversal Nano-Drug Delivery Systems in the Tumor Microenvironment: Mechanisms, Challenges, and Therapeutic Applications.

The charge-reversal nano-drug delivery system (CRNDDS) is a promising system for delivering chemotherapy drugs and has gained widespread application in cancer treatment. In this review, we summarize the recent advancements in CRNDDSs in terms of cancer treatment. We also delve into the charge-reversal mechanism of the CRNDDSs, focusing on the acid-responsive, redox-responsive, and enzyme-responsive mechanisms. This study elucidates how these systems undergo charge transitions in response to specific microenvironmental stimuli commonly found in tumor tissues. Furthermore, this review explores the pivotal role of CRNDDSs in tumor diagnosis and treatment, and their potential limitations. By leveraging the unique physiological characteristics of tumors, such as the acidic pH, specific redox potential, and specific enzyme activity, these systems demonstrate enhanced accumulation and penetration at tumor sites, resulting in improved therapeutic efficacy and diagnostic accuracy. The implications of this review highlight the potential of charge-reversal drug delivery systems as a novel and targeted strategy for cancer therapy and diagnosis.

Oppositely-charged silver nanoparticles enable selective SERS molecular enhancement through electrostatic interactions.

Label-free surface-enhanced Raman spectroscopy (SERS) has attracted extensive attention as an emerging technique for molecular phenotyping of biological samples. However, the selective enhancement property of SERS mediated by complicated interactions between substrates and analytes is unfavorable for molecular profiling. The electrostatic force is among the most dominating interactions that can cause selective adsorption of molecules to charged substrates. This means if only negatively- or positively-charged SERS substrates are applied, then considerable SERS information from a portion of analytes would be lost, hindering comprehensive SERS sensing. In this work, we utilize both negatively- and positively-charged colloidal silver (Ag) nanoparticles (NPs) to detect various charged molecules. The negatively-charged citrate-stabilized Ag and the positively-charged Ag prepared via a cetyltrimethyl-ammonium chloride-based charge reversal protocol have been adopted as SERS substrates. The Ag NPs are all relatively well-dispersed with good uniformity. After applying the oppositely-charged NPs to the detection of charged molecules, we find the SERS results explicitly demonstrate the electrostatically-driven SERS selective enhancement, which is further supported and clarified by molecular electrostatic potential calculations. Our work highlights the importance of developing SERS substrates modified with appropriate surface charges for various analytes, and enlightens us that potentially more molecular SERS information can be acquired from complex bio-samples using combinations of oppositely-charged substrates.

ROS-responsive charge reversal mesoporous silica nanoparticles as promising drug delivery system for neovascular retinal diseases.

Intravitreal injection of biodegradable implant drug carriers shows promise in reducing the injection frequency for neovascular retinal diseases. However, current intravitreal ocular devices have limitations in adjusting drug release rates for individual patients, thereby affecting treatment effectiveness. Accordingly, we developed mesoporous silica nanoparticles (MSNs) featuring a surface that reverse its charge in response to reactive oxygen species (ROS) for efficient delivery of humanin peptide (HN) to retinal epithelial cells (ARPE-19). The MSN core, designed with a pore size of 2.8 nm, ensures a high HN loading capacity 64.4% (w/w). We fine-tuned the external surface of the MSNs by incorporating 20% Acetyl-L-arginine (Ar) to create a partial positive charge, while 80% conjugated thioketal (TK) methoxy polyethylene glycol (mPEG) act as ROS gatekeeper. Ex vivo experiments using bovine eyes revealed the immobilization of Ar-MSNs-TK-PEG (mean zeta potential: 2 mV) in the negatively charged vitreous. However, oxidative stress reversed the surface charge to -25 mV by mPEG loss, facilitating the diffusion of the nanoparticles impeded with HN. In vitro studies showed that ARPE-19 cells effectively internalize HN-loaded Ar-MSNs-TK, subsequently releasing the peptide, which offered protection against oxidative stress-induced apoptosis, as evidenced by reduced TUNEL and caspase3 activation. The inhibition of retinal neovascularization was further validated in an in vivo oxygen-induced retinopathy (OIR) mouse model.

Immunoregulatory Engineering of Semiconducting Charge-Reversal Nanoantioxidant for Ameliorating Cancer Radioimmunotheranostics.

Radiotherapy (RT) is a crucial clinical modality for cancer. However, nonselectivity, toxicity to normal tissues, and radio-resistance severely limit RT applications. This study develops a versatile X-ray theranostic nano-antioxidant (XTN) to prevent normal tissues from oxidative damage and induce systematic and robust anticancer immunity. XTN owns NIR-II photoacoustic (PA) imaging properties for precise discrimination of the tumor margin through, thereby improving the accuracy of RT. Additionally, XTN is a nano-antioxidant to enhance the cell viability of normal cells after irradiation. Most importantly, XTN scavenges reactive oxygen species (ROS) in the TME to preserve the stimulatory activity of released high mobility group protein B1 to dendritic cells (DCs) and recover T cells' immune function. Meanwhile, XTN achieves charge-reversal specifically releasing an immunomodulator (demethylcantharidin, DMC) in the acidic TME. Moreover, the specifically released DMC inhibits protein phosphatase-2A activity and reduces regulatory T cell (Treg) differentiation. In the bilateral 4T1 tumor model, XTN-mediated radioimmunotherapy remarkably boosts a systemic antitumor immune response and induces durable immunological memory against tumor growth.

Metformin-Mediated Fast Charge-Reversal Nanohybrid for Deep Penetration Piezocatalysis-Augmented Chemodynamic Immunotherapy of Cancer.

Immune checkpoint blockade (ICB) therapy still suffers from insufficient immune response and adverse effect of ICB antibodies. Chemodynamic therapy (CDT) has been demonstrated to be an effective way to synergize with ICB therapy. However, a low generation rate of reactive oxygen species and poor tumor penetration of CDT platforms still decline the immune effects. Herein, a charge-reversal nanohybrid Met@BF containing both Fe3O4 and BaTiO3 nanoparticles in the core and Metformin (Met) on the surface was fabricated for tumor microenvironment (TME)- and ultrasound (US)-activated piezocatalysis-chemodynamic immunotherapy of cancer. Interestingly, Met@BF had a negative charge in blood circulation, which was rapidly changed into positive when exposed to acidic TME attributed to quaternization of tertiary amine in Met, facilitating deep tumor penetration. Subsequently, with US irradiation, Met@BF produced H2O2 based on piezocatalysis of BaTiO3, which greatly enhanced the Fenton reaction of Fe3O4, thus boosting robust antitumor immune response. Furthermore, PD-L1 expression was inhibited by the local released Met to further augment the antitumor immune effect, achieving effective inhibitions for both primary and metastatic tumors. Such a combination of piezocatalysis-enhanced chemodynamic therapy and Met-mediated deep tumor penetration and downregulation of PD-L1 provides a promising strategy to augment cancer immunotherapy.

Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: Pronounced efficacy through up-regulation of Wnt/ß-catenin pathway in DMH-induced tumorigenesis.

Celecoxib (CLX), a selective inhibitor for cyclooxygenase 2 (COX-2), has manifested potential activity against diverse types of cancer. However, low bioavailability and cardiovascular side effects remain the major challenges that limit its exploitation. In this work, we developed ultra-elastic nanovesicles (UENVs) with pH-triggered surface charge reversal traits that could efficiently deliver CLX to colorectal segments for snowballed tumor targeting. CLX-UENVs were fabricated via a thin-film hydration approach. The impact of formulation factors (Span 80, Tween 80, and sonication time) on the nanovesicular features was evaluated using Box-Behnken design, and the optimal formulation was computed. The optimum formulation was positively coated with polyethyleneimine (CLX-PEI-UENVs) and then coated with Eudragit S100 (CLX-ES-PEI-UENVs). The activity of the optimized nano-cargo was explored in 1,2-dimethylhydrazine-induced colorectal cancer in Wistar rats. Levels of COX-2, Wnt-2 and ß-catenin were assessed in rats' colon. The diameter of the optimized CLX-ES-PEI-UENVs formulation was 253.62 nm, with a zeta potential of -23.24 mV, 85.64% entrapment, and 87.20% cumulative release (24 h). ES coating hindered the rapid release of CLX under acidic milieu (stomach and early small intestine) and showed extended release in the colon section. In colonic environments, the ES coating layer was removed due to high pH, and the charge on the nanovesicular corona was shifted from negative to positive. Besides, a pharmacokinetics study revealed that CLX-ES-PEI-UENVs had superior oral bioavailability by 2.13-fold compared with CLX suspension. Collectively, these findings implied that CLX-ES-PEI-UENVs could be a promising colorectal-targeted nanoplatform for effective tumor management through up-regulation of the Wnt/ß-catenin pathway.

Enzyme-Responsive Modular Peptides Enhance Tumor Penetration of Quantum Dots via Charge Reversal Strategy.

Quantum dots (QDs) are colloidal semiconductor nanoparticles acting as fluorescent probes for detection, disease diagnosis, and photothermal and photodynamic therapy. However, their performance in cancer treatment is limited by inadequate tumor accumulation and penetration due to the larger size of nanoparticles compared to small molecules. To address this challenge, charge reversal nanoparticles offer an effective strategy to prolong blood circulation time and achieve enhanced endocytosis and tumor penetration. In this study, we leveraged the overexpressed γ-glutamyl transpeptidase (GGT) in many human tumors and developed a library of modular peptides to serve as water-soluble surface ligands of QDs. We successfully transferred the QDs from the organic phase to the aqueous phase within 5 min. And through systematic tuning of the peptide sequence, we optimized the fluorescent stability of QDs and their charge reversal behavior in response to GGT. The resulting optimal peptide stabilized QDs in aqueous solution with a high fluorescent retention rate of 93% after three months and realized the surface charge reversal of QDs triggered by GGT in vitro. The binding between the peptide and QD surface was investigated by using saturation transfer differential nuclear magnetic resonance (STD NMR). Thanks to its charge reversal ability, the GGT-responsive QDs exhibited enhanced cellular uptake in GGT-expressing cancer cells and deeper penetration in the 3D multicellular spheroids. This enzyme-responsive modular peptide can lead to specific tumor targeting and deeper tumor penetration, holding great promise to enhance the treatment efficacy of QD-based theranostics.

Dual-Targeted Graphitic Cascade Nanozymes for Recognition and Treatment of Helicobacter pylori.

Helicobacter pylori (H. pylori) is the major etiological factor of a variety of gastric diseases. However, the treatment of H. pylori is challenged by the destruction of targeted drugs by gastric acid and pepsin. Herein, a dual-targeted cascade catalytic nanozyme PtCo@Graphene@Hemin-2(L-arginine) (PtCo@G@H2A) is designed for the treatment of H. pylori. The dual-targeting ability of PtCo@G@H2A is derived from directly targeting the receptor protein of H. pylori through hemin and responding to the acidic environment to cause charge reversal (protonation of L-arginine) to capture H. pylori, achieving efficient targeting effect. Compared with the single-targeting strategy relying on hemin, the dual-targeting strategy can greatly improve the targeting rate, achieving an increase of 850% targeting rate. At the concentration of NaHCO3 in intestinal fluid, the surface potential of PtCo@G@H2A can be quickly restored to avoid side effects. Meanwhile, PtCo@G@H2A has pH-responsive oxidase-like activity, which can generate nitric oxide (NO) through a cascade catalytic process that first generates reactive oxygen species (ROS) with oxygen, and further oxidizes L-arginine through ROS, realizing a superior acid-selective bactericidal effect. Overall, it proposes a promising strategy for the treatment of H. pylori that maintains high targeting and therapeutic effects in the environment of gastric acid and pepsin.

Charge-Reversible Nanoparticles: Advanced Delivery Systems for Therapy and Diagnosis.

The past two decades have witnessed a rapid progress in the development of surface charge-reversible nanoparticles (NPs) for drug delivery and diagnosis. These NPs are able to elegantly address the polycation dilemma. Converting their surface charge from negative/neutral to positive at the target site, they can substantially improve delivery of drugs and diagnostic agents. By specific stimuli like a shift in pH and redox potential, enzymes, or exogenous stimuli such as light or heat, charge reversal of NP surface can be achieved at the target site. The activated positive surface charge enhances the adhesion of NPs to target cells and facilitates cellular uptake, endosomal escape, and mitochondrial targeting. Because of these properties, the efficacy of incorporated drugs as well as the sensitivity of diagnostic agents can be essentially enhanced. Furthermore, charge-reversible NPs are shown to overcome the biofilm formed by pathogenic bacteria and to shuttle antibiotics directly to the cell membrane of these microorganisms. In this review, the up-to-date design of charge-reversible NPs and their emerging applications in drug delivery and diagnosis are highlighted.

Polyphosphate coated nanoparticles: Enzyme-activated charge-reversal gene delivery systems.

AIM: The current study aimed to develop enzyme-activated charge-reversal lipid nanoparticles (LNPs) as novel gene delivery systems. METHODS: Palmitic acid was covalently bound to protamine being utilised as transfection promoter to anchor it on the surfaces of LNPs. Green fluorescent protein (GFP) encoding plasmid DNA (pDNA) was ion paired with various cationic counter ions to achieve high encapsulation in LNPs. Protamine-decorated LNPs were prepared by solvent injection method followed by coating with sodium tripolyphosphate (TPP) to generate a bio-inert anionic outer surface. Resulting LNPs were characterised regarding size, polydispersity, zeta potential and encapsulation efficiency. Enzyme-triggered charge-reversal of LNPs was investigated using isolated alkaline phosphatase (ALP) monitoring changes in zeta potential as well as monophosphate release. Furthermore, monophosphate release, cell viability and transfection efficiency were evaluated on a human alveolar epithelial (A549) cell line. RESULTS: Protamine-decorated and TPP-coated (Prot-pDNA/DcChol-TPP) LNPs displayed a mean size of 298.8 ± 17.4 nm and a zeta potential of -13.70 ± 0.61 mV. High pDNA encapsulation was achieved with hydrophobic ion pairs of pDNA with 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride (DcChol). Zeta potential of Prot-pDNA/DcChol-TPP LNPs reversed to positive values with a total Δ26.8 mV shift upon incubation with ALP. Conformably, a notable amount of monophosphate was released upon incubation of Prot-pDNA/DcChol-TPP LNPs with isolated as well as cell-associated ALP. A549 cells well tolerated LNPs displaying more than 95 % viability. Compared with naked pDNA, unmodified LNPs and control LNPs, Prot-pDNA/DcChol-TPP LNPs showed a significantly increased transfection efficiency. CONCLUSION: Prot-pDNA/DcChol-TPP LNPs can be regarded as promising gene delivery systems.

Polyzwitterionic micelles with antimicrobial-conjugation for eradication of drug-resistant bacterial biofilms.

The presence of bacterial biofilms has presented a significant challenge to human health. This study presents the development of biofilm microenvironment-responsive polymeric micelles as a novel approach to address the challenges posed by bacterial biofilms. These micelles are composed of two key components: a zwitterionic component, inspired by protein isoelectric points, containing balanced quantities of primary amines and carboxylic groups that undergo a positive charge transformation in acidic microenvironments, and a hydrophobic triclosan conjugate capable of releasing triclosan in the presence of bacterial lipases. Through the synergistic combination of pH-responsiveness and lipase-responsiveness, we have significantly improved drug penetration into biofilms and enhanced its efficacy in killing bacteria. With their remarkable drug-loading capacity and the ability to specifically target and eliminate bacteria within biofilms, these zwitterionic polymeric micelles hold great promise as an effective alternative for treating biofilm-associated infections. Their unique properties enable efficient drug delivery and heightened effectiveness against biofilm-related infections.

Comprehensively Optimizing Fenton Reaction Factors for Antitumor Chemodynamic Therapy by Charge-Reversal Theranostics.

Chemodynamic therapy (CDT) is a highly tumor-specific treatment, while its efficacy is compromised by the intratumoral Fenton reaction efficiency, which is determined by the following reaction factors, including the availability of Fenton ions (e.g., Fe2+), the amount of H2O2, and the degree of acidity. Synchronous optimization of these factors is a big challenge for efficient CDT. Herein, a strategy of comprehensively optimizing Fenton reaction factors was developed for traceable multistage augmented CDT by charge-reversal theranostics. The customized pH-responsive poly(ethylene)glycol-poly(ß-amino esters) (PEG-PAE) micelle (PM) was prepared as the carrier. Glucose oxidase (GOx), Fe2+, and pH-responsive second near-infrared (NIR-II) LET-1052 probe were coloaded by PM to obtain the final theranostics. The activity of metastable Fe2+ remained by the unsaturated coordination with PEG-PAE. Then tumor accumulation and exposure of Fe2+ were achieved by charge-reversal cationization of PEG-PAE, which was further enhanced by a GOx catalysis-triggered pH decrease. Together with the abundant H2O2 generation and pH decrease through GOx catalysis, the limiting factors of the Fenton reaction were comprehensively optimized, achieving the enhanced CDT both in vitro and in vivo. These findings provide a strategy for comprehensively optimizing intratumoral Fenton reaction factors to overcome the intrinsic drawbacks of current CDT.

Artesunate carriers induced ferroptosis to overcome biological barriers for anti-cancer.

Artesunate (ART) has potent anticancer activity but it suffers from poor stability and low bioavailability in vivo due to the special endoperoxide moiety in the molecules. In this work, we fabricated programmable enzyme/reactive oxygen species (ROS) responsive ART complex carriers with size and charge adaptive regulation in order to improve stability and overcome biochemical hurdles of solid tumor. The complex carries (ART/AA-PAMAM@HA) were created by electrostatic interaction between dendrimer-ART/arachidonic acid (AA) (ART/AA-PAMAM) and hyaluronic acid (HA), which can proactively penetrate deeply into tumors and selective drug release. Specifically, ART induced Fenton reaction and produced a mass of ROS and lipid peroxides (LPO), leading to the depressing of GSH level and glutathione peroxidase 4 (GPX4) activity. Meanwhile, exogenous AA further promoted the accumulation of LPO by cascade regulating ferroptosis pathway. In the anti-tumor efficacy in vivo, the tumor inhibition ratio was achieved to 46.92%. This work shows a new anti-tumor strategy triggering ferroptosis via regulating redox homeostasis.

Photo-Enhanced Synergistic Induction of Ferroptosis for Anti-Cancer Immunotherapy.

Ferroptosis as programmed cell death received considerable attention in cancer research. Recently, studies have associated ferroptosis with photodynamic therapy (PDT) because PDT promotes glutathione (GSH) deletion, glutathione peroxidase 4 (GPX4) degradation, and lipid peroxide accumulation. However, PDT-induced ferroptosis may be potentially prevented by ferroptosis suppressor protein 1 (FSP1). To address this limitation, herein, a novel strategy is developed to trigger ferroptosis by PDT and FSP1 inhibition. For enhancement of this strategy, a photoresponsive nanocomplex, self-assembled by BODIPY-modified poly(amidoamine) (BMP), is utilized to stably encapsulate the inhibitor of FSP1 (iFSP1) and chlorin e6 (Ce6). The nanosystem promotes intracellular delivery, penetration, and accumulation of ferroptosis inducers in tumors with light irradiation. The nanosystem presents high-performance triggering of ferroptosis and immunogenic cell death (ICD) in vitro and in vivo. Importantly, the nanoparticles increase tumor infiltration of CD8+ T cells and further enhance the efficacy of anti-PD-L1 immunotherapy. The study suggests the potential of photo-enhanced synergistic induction of ferroptosis by the photoresponsive nanocomplexes in cancer immunotherapy.

A γ-Glutamyl Transpeptidase (GGT)-Triggered Charge Reversal Drug-Delivery System for Cervical Cancer Treatment: In Vitro and In Vivo Investigation.

Neutral/negatively charged nanoparticles are beneficial to reduce plasma protein adsorption and prolong their blood circulation time, while positively charged nanoparticles easily transverse the blood vessel endothelium into a tumor and easily penetrate the depth of the tumor via transcytosis. Γ-Glutamyl transpeptidase (GGT) is overexpressed on the external surface of endothelial cells of tumor blood vessels and metabolically active tumor cells. Nanocarriers modified by molecules containing γ-glutamyl moieties (such as glutathione, G-SH) can maintain a neutral/negative charge in the blood, as well as can be easily hydrolyzed by the GGT enzymes to expose the cationic surface at the tumor site, thus achieving good tumor accumulation via charge reversal. In this study, DSPE-PEG2000-GSH (DPG) was synthesized and used as a stabilizer to generate paclitaxel (PTX) nanosuspensions for the treatment of Hela cervical cancer (GGT-positive). The obtained drug-delivery system (PTX-DPG nanoparticles) was 164.6 ± 3.1 nm in diameter with a zeta potential of -9.85 ± 1.03 mV and a high drug-loaded content of 41.45 ± 0.7%. PTX-DPG NPs maintained their negative surface charge in a low concentration of GGT enzyme (0.05 U/mL), whereas they showed a significant charge-reversal property in the high-concentration solution of GGT enzyme (10 U/mL). After intravenous administration, PTX-DPG NPs mainly accumulated more in the tumor than in the liver, achieved good tumor-targetability, and significantly improved anti-tumor efficacy (68.48% vs. 24.07%, tumor inhibition rate, p < 0.05 in contrast to free PTX). This kind of GGT-triggered charge-reversal nanoparticle is promising to be a novel anti-tumor agent for the effective treatment of such GGT-positive cancers as cervical cancer.

Probing interfacial water structure induced by charge reversal and hydrophobicity of silica surface in the presence of divalent heavy metal ions using sum frequency generation spectroscopy.

HYPOTHESIS: Adsorption of divalent heavy metal ions (DHMIs) at the mineral-water interfaces changes interfacial chemical species and charges, interfacial water structure, Stern (SL), and diffuse (DL) layers. These molecular changes can be detected by probing changing orientation and hydrogen-bond network of interfacial water molecules in response to changing local charges and hydrophobicity. EXPERIMENTS: Sum-frequency generation (SFG) spectroscopy was used to probe changes in vibrational resonances of interfacial OH vs. DHMI concentration and pH. SFG spectra were deconvoluted using the measured surface potential and maximum entropy method in conjunction with the electrical double-layer theory for the SL and DL structures and correlated by hydrophobicity. FINDINGS: Three surface charge reversals (CRs) were detected at low (CR1), medium (CR2), and high (CR3) pHs. Unlike CR1, SFG signals were minimized at CR2 and CR3 for DHMIs-silica systems highlighting considerable alterations in the structure of interfacial waters due to the inner-sphere sorption of metal hydroxo complexes. SFG results showed "hydrophobic-like" stretching modes at > 3600 cm-1 for Pb-, Cu-, and Zn-treated silica. However, contact angle measurements revealed the hydrophobization of silica only in the presence of Pb(II), as confirmed by an in-depth SFG analysis of the hydrogen-bond network of the interfacial water molecules in the SL.

Surface charge adaptive nitric oxide nanogenerator for enhanced photothermal eradication of drug-resistant biofilm infections.

Due to protection of extracellular polymeric substances, the therapeutic efficiency of conventional antimicrobial agents is often impeded by their poor infiltration and accumulation in biofilm. Herein, one type of surface charge adaptable nitric oxide (NO) nanogenerator was developed for biofilm permeation, retention and eradication. This nanogenerator (PDG@Au-NO/PBAM) is composed of a core-shell structure: thermo-sensitive NO donor conjugated AuNPs on cationic poly(dopamine-co-glucosamine) nanoparticle (PDG@Au-NO) served as core, and anionic phenylboronic acid-acryloylmorpholine (PBAM) copolymer was employed as a shell. The NO nanogenerator featured long circulation and good biocompatibility. Once the nanogenerator reached acidic biofilm, its surface charge would be switched to positive after shell dissociation and cationic core exposure, which was conducive for the nanogenerator to infiltrate and accumulate in the depth of biofilm. In addition, the nanogenerator could sustainably generate NO to disturb the integrity of biofilm at physiological temperature, then generate hyperthermia and explosive NO release upon NIR irradiation to efficiently eradicate drug-resistant bacteria biofilm. Such rational design offers a promising approach for developing nanosystems against biofilm-associated infections.

Smart anti-vascular nanoagent induces positive feedback loop for self-augmented tumor accumulation.

How to achieve efficient drug accumulation in the tumor with low vascular density is a great challenge but the key to push the limit of anti-vascular therapeutic efficacy. Herein, we report a charge-reversible nanoparticles of gambogenic acid (CRNP-GNA) that would induce the positive feedback loop between increased tumor vascular permeability and improved drug accumulation. This positive feedback loop would remarkably improve tumor vascular permeability for efficient drug accumulation through few residue vessels. As compared to its charge-irreversible analogue in the latter injections, the accumulation in tumor and vascular permeability and retention indexes (VPRI) in CRNP-GNA group respectively boosted from nearly equal to 8.32 and 60 times, while its tumorous microvessel density decreased from nearly equal to only 7%. The self-augmented accumulation consequently amplified the antitumor efficacy via multiple pathways of anti-angiogenesis, vascular disruption and pro-apoptosis, where 5 out of 6 tumors in animal models were completely cured by CRNP-GNA. This work confirms that the underlying positive feedback loop for anti-vascular therapy could be induced by charge-reversible drug delivery nanosystem to achieve efficient and self-augmented drug accumulation even in the tumor with few vessels. It provides a novel strategy to conquer the dilemma between anti-vascular efficacy and drug accumulation.