Surface Wettability-Switchable Janus Fiber Fragments Stabilize Pickering Emulsions for Effective Oil/Water Separation.

Pickering emulsions indicate stronger resistance against droplet coalescence than the surfactant-stabilized emulsions. To resemble the surfactant amphiphilicity, Janus fiber fragments (JFs) were herein prepared through side-by-side electrospinning of poly(styrene-maleic anhydride) (PSMA) derivatives and cryosection of the aligned fibers, followed by conjugation of hydrophobic cetylamine (C16) and hydrophilic poly(N-isopropylacrylamide) (PNIPAm) ligands on the separate sides. Orthogonal analysis table L25(56) was designed to examine the effect of process parameters on the emulsification efficiency and stability index of Pickering emulsions. The emulsification efficiency is dominated by the JF concentration and length, while the emulsion stability could be prolonged through adjusting the JF concentration and hydrophilic graft density. JF-stabilized emulsions exhibit a much higher stability index (96.4%) than that of Janus microparticle counterparts (37.7%). Though there is no apparent effect on the surface wettability, JFs with PNIPAm grafts of about 2200 Da achieve the most stable Pickering emulsions. Superparamagnetic Fe3O4 nanoparticles are inoculated into JFs to collect emulsion droplets under a magnetic field, and the emulsions could be demulsified at an elevated temperature to harvest oil. Meanwhile, the recovered JF emulsifiers could be repeatedly used without loss of the emulsification efficiency. Thus, this study demonstrates surface-switchable JFs to be effective stabilizers of Pickering emulsions and readily recycled for oil harvesting from wastewater.

Persistent Luminescence-Based Theranostics for Real-Time Monitoring and Simultaneously Launching Photodynamic Therapy of Bacterial Infections.

External light irradiation is usually required in bacterial infection theranostics; however, it is always accompanied by limited light penetration, imaging interference, and incomplete bacterial destruction. Herein, a feasible "image-launching therapy" strategy is developed to integrate real-time optical imaging and simultaneous photodynamic therapy (PDT) of bacterial infections into persistent luminescence (PL) nanoparticles (NPs). Mesoporous silica NPs are used as a substrate for in situ deposition of PL nanodots of ZnGa2 O4 :Cr3+ to obtain mPL NPs, followed by surface grafting with silicon phthalocyanine (Si-Pc) and electrostatic assembly of cyanine 7 (Cy7) to fabricate mPL@Pc-Cy NPs. The PL emission of light-activated mPL@Pc-Cy NPs is quenched by Cy7 assembly at physiological conditions through the fluorescence resonance energy transfer effect, but is rapidly restored after disassembly of Cy7 in response to bacterial infections. The self-illuminating capabilities of NPs avoid tissue autofluorescence under external light irradiation and achieve real-time colorimetric imaging of bacterial infections. In addition, the afterglow of mPL NPs can persistently excite Si-Pc photosensitizers to promote PDT efficacy for bacterial elimination and accelerate wound full recovery with normal histologic features. Thus, this study expands the theranostic strategy for precise imaging and simultaneous non-antibiotic treatment of bacterial infections without causing side effects to normal tissues.

Size-tunable nanogels for cascaded release of metronidazole and chemotherapeutic agents to combat Fusobacterium nucleatum-infected colorectal cancer.

Bacteria play important roles in tumor formation, growth and metastasis through downregulating immune response and initiating drug resistance. Herein, size-tunable nanogels (NGs) have been developed to address the existing size paradox in tumor accumulation, intratumoral penetration and intracellular release of therapeutics for the treatment of Fusobacterium nucleatum (F. nucleatum)-infected colorectal cancer. Zinc-imidazolate frameworks with doxorubicin (DOX) loading and folate grafting (f-ZIFD) were mixed with metronidazole (MET) and encapsulated in NGs through thiol-ene click crosslinking of sulfhydryl hyaluronan, sulfhydryl alginate and 4-arm poly(ethylene glycol) acrylate. Hyaluronidase-initiated matrix degradation causes NG swelling to release sufficient MET and maintains a large size for an extended time period, and the gradually discharged f-ZIFD nanoparticles (NPs) from NGs exhibit acid-responsive intracellular release of DOX after folate-mediated internalization into tumor cells. The encapsulation into NGs significantly enhances the bioavailability and increases half-lives of MET and DOX by around 20 times. In the F. nucleatum-infected tumor model, the extended retention of swollen NGs and the efficient tumor infiltration and cellular uptake of the discharged f-ZIFD NPs cause 6 times higher DOX levels in tumors than that of free DOX administration. F. nucleatum promotes tumor cell proliferation and tumor growth, and the cascaded releases of MET and f-ZIFD NPs eliminate F. nucleatum to effectively inhibit tumor growth with a significant extension of animal survival. Thus, the hyaluronidase-mediated NG expansion and dual-responsive cascaded drug release have overcome challenges in the release regimen and size paradox of drug delivery carriers to combat bacteria-infected cancer.

On-demand bactericidal and self-adaptive antifouling hydrogels for self-healing and lubricant coatings of catheters.

Catheter-related infections are one of the most common nosocomial infections with increasing morbidity and mortality, and robust antibacterial or antifouling catheter coatings remain great challenges for long-term implantation. Herein, multifunctional hydrogel coatings were developed to provide persistent and self-adaptive antifouling and antibacterial effects with self-healing and lubricant capabilities. Polyvinyl alcohol (PVA) with ß-cyclodextrin (ß-CD) grafts (PVA-Cd) and 4-arm polyethylene glycol (PEG) with adamantane and quaternary ammonium compound (QAC) terminals (QA-PEG-Ad) were crosslinked through host-guest recognitions between adamantane and ß-CD moieties to acquire PVEQ coatings. In response to bacterial infections, QACs exhibit reversible transformation between zwitterions (pH 7.4) and cationic lactones (pH 5.5) to generate on-demand bactericidal effect. Highly hydrophilic PEG/PVA backbones and zwitterionic QACs build a lubricate surface and decrease the friction coefficient 10 times compared with that of bare catheters. The antifouling hydrated layer significantly inhibits blood protein adsorption and platelet activation and reveals negligible hemolysis and cytotoxicity. The dynamic host-guest crosslinking achieves full self-healing of cracks in PVEQ hydrogels, and the mechanical profiles were recovered to over 90 % after rejuvenating the broken hydrogels, exhibiting a long-term stability after mechanical stretching, twisting, knotting and compression. After subcutaneous implantation and local bacterial infection, the retrieved PVEQ-coated catheters display no tissue adhesion and 3 log folds lower bacterial number than that of bare catheters. PVEQ coatings effectively prevent the repeated bacterial infections and there are few inflammatory reactions in the surrounding tissue, while substantial lymphoid infiltration and inflammatory cell aggregation occur in muscle tissues around the bare catheter. Thus, this study demonstrates a catheter coating strategy by on-demand bactericidal, self-adaptive antifouling, self-healing and lubricant hydrogels to address medical devices-related infections. STATEMENT OF SIGNIFICANCE: It is estimated over two billion peripheral intravenous catheters are annually used in hospitals around the world, and catheter-associated infection has become a great clinical challenge with rapidly rising morbidity and mortality. Surface coating is considered a promising approach, but substantial challenges remain in the development of coatings that simultaneously satisfy both anti-fouling and antibacterial attributes. Even more, few attempts have been made to design mechanically robust coatings and reversible antibacterial or antifouling capabilities, which are critical for long-term medical implants. To address these challenges, we propose a concise strategy to develop hydrogel coatings from commercially available poly(ethylene glycol) and polyvinyl alcohol. In addition to self-healing and lubricant capabilities, the reversible conversion between zwitterionic and cationic lactones of quaternary ammonium compounds enables on-demand bactericidal and self-adaptive antifouling effects.

Dual-Responsive Nanogels with Cascaded Gentamicin Release and Lysosomal Escape to Combat Intracellular Small Colony Variants for Peritonitis and Sepsis Therapies.

Intracellular bacteria are the major cause of serious infections including sepsis and peritonitis, but face great challenges in fighting against the stubborn intracellular small colony variants (SCVs). Herein, the authors have developed nanogels (NGs) to destroy both planktonic bacteria and SCVs and eliminate excessive inflammations for peritonitis and sepsis therapies. Free gentamicin (GEN) and hydroxyapatite nanoparticles (NPs) with GEN loading and mannose grafts (mHAG) are inoculated into ε-polylysine NGs to obtain NG@G1-mHAG2 through crosslinking with phenylboronic acid and tannic acid. The H2O2 consumption after reaction with phenylboronic esters and the elimination of free radicals by tannic acid alleviates the escalated inflammatory status to promote sepsis therapy. After mannose-mediated uptake into macrophages, the acid-triggered degradation of mHAG NPs generates Ca2+ to destabilize lysosomes and the efficient lysosomal escape leads to reversion of hypometabolic SCVs into normal phenotype and their sensitivity to GEN. In a peritonitis mouse model, NG@G1-mHAG2 treatment provides strong and persistent bactericidal effects against both extracellular bacteria and intracellular SCVs and extends survival of peritonitis mice without apparent hepatomegaly, splenomegaly, pulmonary edema, and inflammatory cell infiltration. Thus, this study demonstrates a concise and versatile strategy to eliminate SCVs and relieve inflammatory storms for peritonitis and sepsis therapies without infection recurrence.

Injectable cell-targeting fiber rods to promote lipolysis and regulate inflammation for obesity treatment.

Obesity has become a worldwide public health problem and continues to be one of the leading causes of chronic diseases. Obesity treatment is challenged by large drug doses, high administration frequencies and severe side effects. Herein, we propose an antiobesity strategy through the local administration of HaRChr fiber rods loaded with chrysin and grafted with hyaluronic acid and AtsFRk fiber fragments loaded with raspberry ketone and grafted with adipocyte target sequences (ATSs). The hyaluronic acid grafts double the uptake levels of HaRChr by M1 macrophages to promote phenotype transformation from M1 to M2 through upregulating CD206 and downregulating CD86 expressions. ATS-mediated targeting and sustained release of raspberry ketone from AtsFRk increase the secretion of glycerol and adiponectin, and Oil red O staining shows much fewer lipid droplets in adipocytes. The combination treatment with AtsFRk and the conditioned media from HaRChr-treated macrophages elevates adiponectin levels, suggesting that M2 macrophages may secrete anti-inflammatory factors to stimulate adipocytes to produce adiponectin. Diet-induced obese mice showed significant weight losses of inguinal (49.7%) and epididymal (32.5%) adipose tissues after HaRChr/AtsFRk treatment, but no effect was observed on food intake. HaRChr/AtsFRk treatment reduces adipocyte volumes, lowers serum levels of triglycerides and total cholesterol and restores adiponectin levels to those of normal mice. In the meantime, HaRChr/AtsFRk treatment significantly elevates the gene expression of adiponectin and interleukin-10 and downregulates tissue necrosis factor-α expression in the inguinal adipose tissues. Thus, local injection of cell-targeting fiber rods and fragments demonstrates a feasible and effective antiobesity strategy through improving lipid metabolism and normalizing the inflammatory microenvironment.

Ultrasound-Chargeable Persistent Luminescence Nanoparticles to Generate Self-Propelled Motion and Photothermal/NO Therapy for Synergistic Tumor Treatment.

Cancer phototherapy indicates advantages in ease of manipulation, negligible drug resistance, and spatiotemporal control but is confronted with challenges in tumor cell accessibility and intermittent light excitation. Herein, we propose a strategy with persistent luminescence (PL)-excited photothermal therapy (PTT), concurrent thermophoresis-propelled motion, and PL-triggered NO release, where PL emission is chargeable by ultrasonication for readily applicable to deep tumors. Mechanoluminescent (ML) nanodots of SrAl2O4:Eu2+ (SAOE) and PL nanodots of ZnGa2O4:Cr3+ (ZGC) were deposited on mesoporous silicates to obtain mSZ nanoparticles (NPs), followed by partially coating with polydopamine (PDA) caps and loading NO donors to prepare Janus mSZ@PDA-NO NPs. The ML emission bands of SAOE nanodots overlap with the excitation band of ZGC, and the persistent near-infrared (NIR) emission could be repeatedly activated by ultrasonication. The PL emission acts as an internal NIR source to produce a thermophoretic force and NO gas propellers to drive the motion of Janus NPs. Compared with the commonly used intermittent NIR illumination at both 660 and 808 nm, the persistent motion of ultrasound-activated NPs enhances cellular uptake and long-lasting PTT and intracellular NO levels to combat tumor cells without the use of any chemotherapeutic drugs. The ultrasound-activated persistent motion promotes intratumoral accumulation and tumor distribution of PTT/NO therapeutics and exhibits significantly higher tumor growth inhibition, longer animal survival, and larger intratumoral NO levels than those who experience external NIR illumination. Thus, this study demonstrates a strategy to activate PL emissions and construct PL-excited nanomotors for phototherapy in deep tissues.

Self-Propelling Nanomotors Integrated with Biofilm Microenvironment-Activated NO Release to Accelerate Healing of Bacteria-Infected Diabetic Wounds.

Diabetic foot ulcer (DFU) treatment is challenged by persistent bacterial infection and hyperglycemia-caused vascular dysplasia. Herein, self-propelled nanomotors are designed to achieve biofilm microenvironment (BME)-activated multistage release of NO for effective sterilization and subsequent angiogenesis promotion. CaO2 nanoparticles (NPs) are capped with PDA layers, followed by complexation with Fe2+ and surface grafting of cysteine-NO to obtain Janus Ca@PDAFe -CNO NPs. In response to low pH in BME, the decomposition of CaO2 cores generates O2 from one side of Janus NPs to propel biofilm penetration, and the released H2 O2 and Fe2+ produce •OH through Fenton reaction. The concurrent glutathione-triggered release of NO can be converted into reactive nitrogen species, which exhibit significantly higher bactericidal efficacy than those with only generation of •OH or NO. The slow release of NO for an extended time period promotes endothelial cell proliferation and migration. On Staphylococcus aureus-infected skin wounds of diabetic mice, NP treatment eliminates bacterial infections and significantly elevates blood vessel densities, leading to full wound recovery and regeneration of arranged collagen fibers and skin accessories. Thus, the self-propelling and multistage release of NO provide a feasible strategy to combat biofilm infection without using any antibiotics and accelerate angiogenesis and wound healing for DFU treatment.

Intracellular infection-responsive release of NO and peptides for synergistic bacterial eradication.

Bacteria have the ability to invade and survive in host cells to form intracellular bacteria (ICBs), and challenges remain in the intracellular delivery of sufficient antibiotics to remove ICBs. Herein, antimicrobial peptide of epsilon-poly-l-lysine (ePL) and nitric oxide (NO) donors are integrated into nanoparticles (NPs) for ICB treatment without using any antibiotics. ePL was grafted with dodecyl alcohol through ethyl dichlorophosphate to prepare ePL-C12, followed by conjugation of nitrate-functionalized NO donors to obtain ePL-C12NO. PNO/C NPs were prepared from mixtures of ePL-C12NO and ePL-C12 and the optimal ePL-C12NO ratio was 7% in terms of bactericidal effect and macrophage toxicity. Once being engulfed by bacteria-infected macrophages (BIMs), NPs are disintegrated when encountering with ICB-secreted phosphatase, and the NP degradation accelerates intracellular NO release in response to the elevated glutathione levels in BIMs. The selective and abrupt release of NO and ePL with different antimicrobial mechanisms exhibits synergistic eradication of ICBs and no apparent toxicity to macrophages. ICB-infected mice show persistent weight loss and 100% of mortality rate after treatment with ePL-C12 NPs for 7 days, while PNO/C treatment causes entire survival of infected mice and full recovery of body weights to normal values. ICB-infected mice are also accompanied with apparent hepatomegaly and splenomegaly, which are only eliminated by PNO/C treatment without associated any pathological abnormality. PNO/C treatment reduces bacterial burdens in livers (2.45 log), spleens (2.16 log) and kidneys (3.46 log) and restores hepatic and renal function to normal levels. Thus, this study provides a feasible strategy to selectively release NO and cationic peptides in response to intracellular infection-derived signals, achieving synergistic eradication of ICBs and function restoration of the main tissues.

On-Demand Changeable Theranostic Hydrogels and Visual Imaging-Guided Antibacterial Photodynamic Therapy to Promote Wound Healing.

Antibacterial wound dressings are confronted with the challenges in real-time imaging of infected wounds and effective removal of bacterial debris after sterilization to promote the healing process. Herein, injectable theranostic hydrogels were constructed from antimicrobial peptide ε-polylysine (ePL) and polydopamine (PDA) nanoparticles for real-time diagnosis of infected wounds, imaging-guided antibacterial photodynamic therapy (PDT), and on-demand removal of bacterial debris. Ureido-pyrimidinone was conjugated on ePL to produce PLU hydrogels through quadruple hydrogen bonding, and the inoculation of tetrakis(4-carboxyphenyl)porphyrin (TCPP)-loaded PDA (PTc) nanoparticles introduced Schiff base linkages in PLU@PTc hydrogels. The double-cross-linked networks enhance mechanical performance, adhesion strength, and self-healing properties of hydrogels, and the dynamic cross-linking enables their photothermal removal. The injection of PLU precursors and PTc NPs generates in situ sol-gel transformation, and the acid-triggered release of TCPP restores fluorescence emissions for real-time imaging of infected wounds under 410 nm illumination. Then, the released TCPP in the infected wounds is illuminated at 660 nm to launch a precise antibacterial PDT, which is strengthened by the bacterial capture on hydrogels. Hydrogels with wrapped bacterial debris are removed under illumination at 808 nm, and the hydrogel dressing change accelerates healing of infected wounds through simultaneous relief of oxidative stress, regulation of inflammatory factors, acceleration of collagen deposition, and promotion of angiogenesis. Thus, this study demonstrates a feasible strategy for wound infection theranostics through bacterial infection-triggered visual imaging, efficient nonantibiotic sterilization, and on-demand dressing change and bacterial debris removal.

Bacteria-Templated and Dual Enzyme-Powered Microcapsule Motors To Promote Thrombus Penetration and Thrombolytic Efficacy.

Antithrombotic therapy is confronted with short half-lives of thrombolytic agents and high bleeding risks. Challenges remain in the development of drug delivery systems for thorough destruction of thrombi and timely restoration of blood flow while minimizing side effects. Herein, polydopamine capsule-like micromotors with urokinase (uPA) loadings and Arg-Gly-Asp (RGD) grafts (r-u@PCM) were constructed using rod-shaped bacteria as the template, and one single opening was created on each capsule through bacterial ghost (BG) formation. Glucose oxidase and catalase were encapsulated in the large cavity of microcapsules, and their successive oxidation of glucose produced O2 bubbles, which ejected out through the single opening to propel the motion of r-u@PCM. In vitro targeting testing of r-u@PCM shows significant higher accumulations on the activated platelets than those without RGD grafts (u@PCM, 7 folds) or without enzyme loadings (r-u@PC, 11 folds). Compared with the major distribution of r-u@PC on the clot surface, r-u@PCM efficiently penetrates into clots with dense fibrin networks, and near-infrared (NIR) irradiation (r-u@PCM/NIR) promotes thrombus infiltration through increasing uPA release and thermolysis of the networks. Pharmacokinetic study shows that the loading of uPA in r-u@PCM extends the terminal half-life from 24 min to 5.5 h and the bioavailability increased 13 times. In a hindlimb venous thrombosis model, r-u@PCM/NIR treatment promotes uPA accumulations in thrombi and disrupts all the thrombi after 8 h with a full recovery of blood flows. Effective thrombolysis is also achieved even after reducing the uPA dose 5 times. Thus, this is the first attempt to fabricate rod-shaped microcapsule motors through a biologically derived method, including bacterial templating and BG formation-induced opening generation. r-u@PCM/NIR treatment promotes thrombolysis through the photothermal effect, self-propelled infiltration into thrombi, and accelerated local release of uPA, providing a prerequisite for reducing uPA dose and bleeding side effects.

Bacteria-propelled microtubular motors for efficient penetration and targeting delivery of thrombolytic agents.

Effective thrombolysis is critical to rapidly rebuild blood flow for thrombosis patients. Drug delivery systems have been developed to address inadequate pharmacokinetics of thrombolytic agents, but challenges still remain in the timely removal of blood clots regarding the dense fibrin networks. Herein, rod-shaped tubular micromotors were developed to achieve efficient penetration and thorough destruction of thrombi. By using electrospun fiber fragments as the template, urokinase (uPA)-loaded polydopamine (PDA) microtubes with surface decorated fucoidan (FuPDAuPA) were prepared at the aspect ratio of around 2. One E. coli Nissle 1917 (EcN) was assembled into one microtube to construct a FuPDAuPA@EcN hybrid micromotor through PDA adhesion and L-aspartate induction. The pharmacokinetic analysis indicates that the encapsulation of uPA into micromotors extends the half-life from 0.4 to 5.6 h and increases the bioavailability over 10 times. EcN-propelled motion elevates adsorption capacities of FuPDAuPA@EcN for more than four times compared with that of FuPDAuPA. The fucoidan-mediated targeting causes 2-fold higher thrombolysis capacity in vitro and over 10-fold higher uPA accumulation in thrombi in vivo. In the treatment of venous thrombi at mouse hindlimbs, intravenous administration of FuPDAuPA@EcN completely removed blood clots with almost full recovery of blood flows and apparently alleviated tail bleeding. It should be noted that FuPDAuPA@EcN treatment at a reduced uPA dose caused no significant difference in the blood flow rate compared with those of FuPDAuPA. The synergistic action of fucoidan-induced targeting and EcN-driven motion provides a prerequisite for promoting thrombolytic efficacy and reducing uPA dose and bleeding side effect. STATEMENT OF SIGNIFICANCE: The standard treatment to thrombosis patient is intravenous infusion of thrombolytic agents, but the associated bleeding complications and impairment of normal haemostasis greatly offset the therapeutic benefits. Drug delivery systems have been developed to address the limitations of inadequate pharmacokinetics of thrombolytic agents, but challenges still exist in less efficient penetration into dense networks for thorough destruction of thrombi. Up to now only few attempts have been made to construct nano-/micromotors for combating thrombosis and there is no single case that antithrombosis is assisted by bacteria or cells-propelled motors. Herein, bacteria-propelled microtubes were developed to carry urokinase for efficient penetration into blood clots and effective thrombolysis. The synergistic action of bacteria-driven motion and specific ligand-induced targeting holds a promising treatment strategy for life-threatening cardiovascular diseases such as thrombosis and atherosclerosis.

Ultrasound-Propelled Janus Rod-Shaped Micromotors for Site-Specific Sonodynamic Thrombolysis.

Antithrombosis therapy is confronted with short half-lives of thrombolytic agents, limited therapeutic effects, and bleeding complications. Drug delivery systems of thrombolytic agents face challenges in effective penetration into thrombi, which are characterized by well-organized fibrin filled with abundant activated platelets. Herein, Janus rod (JR)-shaped micromotors are constructed by side-by-side electrospinning and cryosection, possessing advantages in controlling the Janus structure and aspect ratio of microrods. Silicon phthalocyanine (Pc) and CaO2 nanoparticles (NPs) are loaded into the separate sides of JRs, and Arg-Gly-Asp (RGD) peptides are grafted on the surface to obtain Pc/Ca@r-JRs for the sonodynamic therapy (SDT) of thrombosis without using any thrombolytic agents. Decomposition of CaO2 NPs ejects O2 bubbles from one side of JRs, and ultrasonication of O2 bubbles produces the cavitation effect, both generating mechanical force to drive the thrombus penetration. The integration of ultrasonication-propelled motion and RGD mediation effectively increases the targeting capabilities of r-JRs to activated platelets. In addition to mechanical thrombolysis, ultrasonication of the released Pc produces 1O2 to destruct fibrin networks of clots. In vitro thrombolysis of whole blood clots shows that ultrasonication of Pc/Ca@r-JRs has a significantly higher thrombolysis rate (73.6%) than those without propelled motion or RGD-mediated clot targeting. In a lower limb thrombosis model, intravenous administration of Pc/Ca@r-JRs indicates 3.4-fold higher accumulations at the clot site than those of JRs, and ultrasonication-propelled motion further increases thrombus retention 2.1 times. Treatment with Pc/Ca@r-JRs and ultrasonication fully removes thrombi and significantly prolongs tail bleeding time. Thus, this study has achieved precise and prompt thrombolysis through selective targeting to clots, efficient penetration into dense networks of thrombi, and SDT-executed thrombolysis.

Surface decoration of black phosphorus nanosheets to generate oxygen and release 1O2 for photodynamic killing of bacteria.

Photodynamic therapy (PDT) has evolved as an essential method for infection control, but is confronted with challenges in terms of low oxygen supply, possible toxicity during light irradiation, and nonpersistent action. Herein, to address these limitations, black phosphorus (BP) is used as a photosensitizer and decorated with Pt nanoparticles and aminobenzyl-2-pyridone (APy) moieties to obtain BP@APy-Pt. The stability of BP is improved through the capture and occupation of lone-pair electrons after reductive deposition of Pt nanoparticles and covalent conjugation of APy. Pt nanoparticles on BP@APy-Pt catalyze the decomposition of endogenous H2O2 to produce oxygen for consecutive cycles with a stable production capacity. The light exposure to BP@APy-Pt generates significantly higher 1O2 levels than those of BP/light, and the generated 1O2 is partially captured by APy moieties. The captured 1O2 during 20 min of illumination shows a constant release for 24 h in the dark. The cycled storage and release feature eliminates the toxicity of 1O2 at high levels during illumination and leads to efficient destruction of S. aureus and P. aeruginosa. Compared to the healing rates after treatment with BP/light (57.6%), BP@Pt/light (64.8%), BP@APy/light (77.8%), and BP@APy-Pt (48.5%), the skin wounds with infected S. aureus are fully healed after BP@APy-Pt/light treatment. Blood vessels and hair follicles are regenerated to resemble those of normal skin. Thus, this study expands the PDT strategy through integration with oxygen generation, 1O2 storage, and persistent release to promote bactericidal efficacy and eliminate side effects.

Shape switching of CaCO3-templated nanorods into stiffness-adjustable nanocapsules to promote efficient drug delivery.

Geometry and mechanical property have emerged as important parameters in designing nanocarriers, in addition to their size, surface charge, and hydrophilicity. However, inconsistent and even contradictory demands regarding the shape and stiffness of nanoparticles have been noted in blood circulation, tumor accumulation, and tumor cell internalization. Herein, CaCO3 nanorods (NRs) with an aspect ratio of around 2.4 are assembled with hyaluronic acid (HA) hydrogel layers to prepare CaCO3@HA NRs. The rod geometry enables lower recognition by macrophages and higher extravasation into tumor tissues than the spherical counterpart. In response to the slightly acidic tumor matrix, the acid-labile removal of CaCO3 templates achieves shape switching into spherical HA nanocapsules (NCs). The shape switchable CaCO3@HA NRs show significantly higher uptake and cytotoxicities to 4T1 cells than CaCO3-Si@HA NRs with silica layers on CaCO3 cores to inhibit shape switching. In addition, HA NCs with 2 - 8 layers of HA hydrogels exhibit stiffness from 1.85 to 12.3 N/m, and the assembly of 4 layers shows 2- to 3-fold higher cellular uptake than those of other NCs. The shape shift satisfies long-term blood circulation of NRs, and the resulting stiffness-adjustable NCs promote tissue infiltration and intracellular accommodation, resulting in a 4-fold higher drug accumulation in tumors. The CaCO3@HA NR treatment significantly suppresses tumor growth; prolongs animal survival; inhibits lung metastasis; and eliminates systemic toxicities to blood, liver, kidney, and heart tissues. This study achieves a comprehensive understanding of the shape and stiffness effects and demonstrates a hierarchical targeting strategy to address the multiple delivery barriers for chemotherapeutic agents. STATEMENT OF SIGNIFICANCE: The different barriers involved in the drug delivery pathway have inconsistent and even contradictory demands on the shape and stiffness of nanoparticles. In the current study, in situ switching of nanorods (NRs) into spherical nanocapsules (NCs) in tumor tissues is proposed to address these dilemmas. The NR shape ensures long-term blood circulation and high tumor tissue accumulation, while the in situ switching into NCs promotes tissue infiltration and cellular internalization. NCs with different numbers of hydrogel layers also provide a robust system wherein NC stiffness is controlled as a single variable to study stiffness-dependent cellular behaviors. Thus, this straightforward design offers a comprehensive understanding of how the shape and stiffness of nanocarriers affect their biological pathways.

Icebreaker-inspired Janus nanomotors to combat barriers in the delivery of chemotherapeutic agents.

Cancer chemotherapy remains challenging to pass through various biological and pathological barriers such as blood circulation, tumor infiltration and cellular uptake before the intracellular release of antineoplastic agents. Herein, icebreaker-inspired Janus nanomotors (JMs) are developed to address these transportation barriers. Janus nanorods (JRs) are constructed via seed-defined growth of mesoporous silica nanoparticles on doxorubicin (DOX)-loaded hydroxyapatite (HAp) nanorods. One side of JRs is grafted with urease as the motion power via catalysis of physiologically existed urea, and hyaluronidase (HAase) is on the other side to digest the viscous extracellular matrices (ECM) of tumor tissues. The rod-like feature of JMs prolongs the blood circulation, and the self-propelling force and instantaneous digestion of hyaluronic acid along the moving paths promote extravasation across blood vessels and penetration in tumor mass, leading to 2-fold higher drug levels in tumors after JM administration than those with JRs. The digestion of ECM in the diffusion paths is more effective to enhance drug retention and diffusion in tumors compared with enzyme-mediated motion. The ECM digestion and motion capabilities of JMs show no influence on the endocytosis mechanism, but lead to over 3-fold higher cellular uptake than those of pristine JRs. The JM treatment promotes therapeutic efficacy in terms of survival prolongation, tumor growth inhibition and cell apoptosis induction and causes no tumor metastasis to lungs with normal alveolar spaces. Thus, the self-driven motion and instantaneous clearance of diffusion routes demonstrate a feasible strategy to combat a series of biological barriers in the delivery of chemotherapeutic agents in favor of antitumor efficacy.

Hierarchically targetable fiber rods decorated with dual targeting ligands and detachable zwitterionic coronas.

The shapes of drug carriers have significant effects on the drug's blood circulation lifetime and tumor accumulation levels. In this study, nonspherical drug carriers of fiber rods are enhanced with hierarchically targeting capabilities to achieve long circulation in blood, on-demand recovery of cell targeting ligands in tumor tissues and dual ligands-mediated cellular uptake. Zwitterionic polymers are conjugated on fiber rods via acid-labile linkers as stealth coronas to reduce the capture by macrophages and shield the targeting ligands. Compared with commonly used poly(ethylene glycol), the zwitterionic grafts show significantly higher inhibition of protein adsorption and lower internalization by macrophages, leading to around 2 folds longer blood circulation and over 2.5 folds higher drug accumulation in tumors than pristine fiber rods. To address the conflicts between blood circulation and cellular uptake, the zwitterionic coronas are efficiently removed in the slightly acidic tumor microenvironment. The exposure of targeting ligands could activate the internalization by tumor cells, resulting in higher cytotoxicity and tumor accumulation than those with stable linkers. Fiber rods are grafted with dual ligands of folate and biotin, and the optimal ligand densities and ratios are determined to maximize the tumor cell uptake. Compared with other treatment, fiber rods with decorated zwitterionic coronas and acid-liable exposure of dual targeting ligands enhance the suppression of tumor growth, prolong animal survival, and cause less lung metastasis. The development of fiber rods with hierarchically targeting capabilities shows great potential in improving the blood circulation, tumor accumulation and cellular uptake, and eventually promoting therapeutic efficacy. STATEMENT OF SIGNIFICANCE: The targeted delivery of chemotherapeutic agents will encounter a series of biological and pathological barriers. In this study, fiber rods were empowered with hierarchically targeting capabilities to resolve the conflict between blood circulation and cellular uptake. This strategy has shown several advantages over the existing methods. Firstly, zwitterionic polymers were used as blood circulation ligands, and concrete evidence was provided via head-to-head comparison with commonly used poly(ethylene glycol) ligands in the macrophage uptake and in vivo tissue distribution. Secondly, the depletion of circulation ligands and on-demand exposure of targeting ligands in tumor tissues showed crucial effects on the uptake by tumor cells. Thirdly, the densities and ratios of the dual targeting ligands were initially determined for a maximal cellular internalization.