pH-Responsive Wound Dressing Based on Biodegradable CuP Nanozymes for Treating Infected and Diabetic Wounds.

Nanozymes, emerging nanomaterials for wound healing, exhibit enzyme-like activity to modulate the levels of reactive oxygen species (ROS) at wound sites. Yet, the solo regulation of endogenous ROS by nanozymes often falls short, particularly in chronic refractory wounds with complex and variable pathological microenvironments. In this study, we report the development of a multifunctional wound dressing integrating a conventional alginate (Alg) hydrogel with a newly developed biodegradable copper hydrogen phosphate (CuP) nanozyme, which possesses good near-infrared (NIR) photothermal conversion capabilities, sustained Cu ion release ability, and pH-responsive peroxidase/catalase-mimetic catalytic activity. When examining acute infected wounds characterized by a low pH environment, the engineered Alg/CuP composite hydrogels demonstrated high bacterial eradication efficacy against both planktonic bacteria and biofilms, attributed to the combined action of catalytically generated hydroxyl radicals and the sustained release of Cu ions. In contrast, when applied to chronic diabetic wounds, which typically have a high pH environment, these composite hydrogels exhibit significant angiogenic performance. This is driven by the provision of catalytically generated dissolved oxygen and a beneficial supplement of Cu ions released from the degradable CuP nanozyme. Further, a mild thermal effect induced by NIR irradiation amplifies the catalytic activities and bioactivity of Cu ions, thereby enhancing the healing process of both infected and diabetic wounds. Our study validates that the synergistic integration of photothermal effects, catalytic activity, and released Cu ions can concurrently yield high antibacterial efficiency and tissue regenerative activity, rendering it highly promising for various clinical applications in wound healing.

Oxidative Stimuli-Responsive "Pollen-Like" Exosomes from Silver Nanoflowers Remodeling Diabetic Wound Microenvironment for Accelerating Wound Healing.

The hostile oxidative wound microenvironment, defective angiogenesis, and uncontrolled release of therapeutic factors are major challenges in improving the diabetic wound healing. Herein, adipose-derived-stem-cell-derived exosomes (Exos) are first loaded into Ag@bovine serum albumin (BSA) nanoflowers (Exos-Ag@BSA NFs) to form a protective "pollen-flower" delivery structure, which are further encapsulated into the injectable collagen (Col) hydrogel (Exos-Ag@BSA NFs/Col) for concurrent remodeling of the oxidative wound microenvironment and precise release of Exos. The Exos-Ag@BSA NFs can selectively dissociate in an oxidative wound microenvironment, which triggers sustained release of Ag ions (Ag+ ) and cascades controllable release of "pollen-like" Exos at the target site, thus protecting Exos from oxidative denaturation. Such a wound-microenvironment-activated release property of Ag+ and Exos effectively eliminates bacteria and promotes the apoptosis of impaired oxidative cells, resulting in improved regenerative microenvironment. Additionally, Exos-Ag@BSA NFs/Col markedly accelerates wound healing and regeneration in vivo in a diabetic murine silicone-splinted excisional wound model by promoting blood perfusion, tissue granulation, collagen deposition, neovascularization, angiogenesis, and re-epithelization. It is anticipated that this work will inspire the development of more delicate and disease-specific therapeutic systems for clinical wound management.

Reversing Immune Suppression and Potentiating Photothermal Immunotherapy via Bispecific Immune Checkpoint Inhibitor Loaded Hollow Polydopamine Nanospheres.

Despite the great achievements of immune checkpoint blockade (ICB) therapy on programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis, ICB monotherapy still faces obstacles in eradicating solid tumors due to the lack of tumor-associated antigens or tumor-specific cytotoxicity. Photothermal therapy (PTT) is a potential therapeutic modality because it can noninvasively kill tumor cells by thermal ablation and generate both tumor-specific cytotoxicity and immunogenicity, which holds great feasibility to improve the efficiency of ICB by providing complementary immunomodulation. Except for the PD-1/PD-L1 axis, the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) pathway has been considered as a novel strategy of tumor cells to evade the surveillance of macrophages and inactivate the immune response of PD-L1 blockade therapy. Therefore, it is necessary to synergize the antitumor effect of dual-targeting PD-L1 and CD47. Although promising, the application of PD-L1/CD47 bispecific antibodies, especially in combination with PTT, remains a formidable problem, due to the low objective response, activity loss at relatively high temperature, or nonvisualization. Herein, instead of using antibodies, we use MK-8628 (MK) to down-regulate both PD-L1 and CD47 simultaneously through halting the active transcription of oncogene c-MYC, leading to elicitation of the immune response. The hollow polydopamine (HPDA) nanospheres are introduced as a biocompatible nanoplatform with high loading capacity and magnetic resonance imaging (MRI) ability to deliver MK and induce PTT (HPDA@MK). Compared to preinjection, HPDA@MK exhibits the strongest MRI signal at 6 h postintravenous injection to guide the precise combined treatment time. However, due to the local delivery and controlled release of inhibitors, HPDA@MK down-regulates c-MYC/PD-L1/CD47, promotes the activation and recruitment of cytotoxic T cells, regulates the M2 macrophages polarization in tumor sites, and especially boosts the combined therapeutic efficacy. Collectively, our work presents a simple but distinctive approach for c-MYC/PD-L1/CD47-targeted immunotherapy combined with PTT that may provide a desirable and feasible strategy for the treatment of other clinical solid tumors.

Self-Assembled Carrier-Free Nanodrugs for Starvation Therapy-Amplified Photodynamic Therapy of Cancer.

Traditional starvation treatment strategies, which involve glucose oxidase and drug-induced thrombi, often suffer from aggravated tumor hypoxia and have failed to improve antitumor efficacy in combination with oxygen-dependent photodynamic therapy (PDT). Herein, glucose transporter 1 inhibitor genistein (Gen) and photosensitizer chlorin e6 (Ce6) are integrated to construct carrier-free self-assembled nanoparticles defined as GC NPs, for starvation therapy-amplified PDT of tumor. GC NPs with regular morphology and stability are screened out by component adjustment, while the function of each component is preserved. On the one hand, Gen released from GC NPs can cut off tumor glucose uptake by inhibiting the glucose transporter 1 to restrict tumor growth, achieving starvation therapy. On the other hand, they are able to decrease the amount of oxygen consumed by tumor respiration and amplify the therapeutic effect of PDT. In vitro and in vivo experiments verify the excellent synergistic antitumor therapeutic efficacy of GC NPs without any apparent toxicity. Moreover, fluorescence and photoacoustic imaging provide guidance for in vivo PDT, demonstrating the excellent tumor enrichment efficiency of GC NPs. It is believed that this starvation therapy-amplified PDT strategy by carrier-free self-assembled GC NPs holds promising clinical prospects.

Precision Delivery of Dual Immune Inhibitors Loaded Nanomodulator to Reverse Immune Suppression for Combinational Photothermal-Immunotherapy.

Although photothermal therapy (PTT) can noninvasively kill tumor cells and exert synergistic immunological effects, the immune responses are usually harmed due to the lack of cytotoxic T cells (CTLs) pre-infiltration and co-existing of intricate immunosuppressive tumor microenvironment (TME), including the programmed cell death ligand 1 (PD-L1)/cluster of differentiation 47 (CD47)/regulatory T cells (Tregs)/M2-macrophages overexpression. Indoleamine 2, 3-dioxygenase inhibitor (NLG919) or bromodomain extra-terminal inhibitor (OTX015) holds great promise to reprogram suppressive TME through different pathways, but their collaborative application remains a formidable challenge because of the poor water solubility and low tumor targeting. To address this challenge, a desirable nanomodulator based on dual immune inhibitors loaded mesoporous polydopamine nanoparticles is designed. This nanomodulator exhibits excellent biocompatibility and water solubility, PTT, and bimodal magnetic resonance/photoacoustic imaging abilities. Owing to enhanced permeability and retention effect and tumor acidic pH-responsiveness, both inhibitors are precisely delivered and locally released at tumor sites. Such a nanomodulator significantly reverses the immune suppression of PD-L1/CD47/Tregs, promotes the activation of CTLs, regulates M2-macrophages polarization, and further boosts combined therapeutic efficacy, inducing a strong immunological memory. Taken together, the nanomodulator provides a practical approach for combinational photothermal-immunotherapy, which may be further broadened to other "immune cold" tumors.

Mild Heat-Assisted Polydopamine/Alginate Hydrogel Containing Low-Dose Nanoselenium for Facilitating Infected Wound Healing.

In clinical practice, it has become urgent to develop multifunctional wound dressings that can combat infection and prompt wound healing simultaneously. In this study, we proposed a polydopamine/alginate/nanoselenium composite hydrogel (Alg-PDA-Se) for the treatment of infected wounds. In particular, polydopamine endows the composite hydrogel with controllable near-infrared photothermal properties, while low-dosage selenium nanoparticles (Se NPs) offer excellent anti-oxidation, anti-inflammatory, pro-proliferative, pro-migration, and pro-angiogenic performances, which are verified by multiple cells, including macrophages, fibroblasts, and endothelial cells. More interestingly, the combination of mild temperature with low-dosage Se NPs produces a synergistic effect on combating both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) and promoting the healing of bacteria-infected wounds in vivo. We anticipate that the designed composite hydrogel might be a potential candidate for anti-infection bioactive dressing.

Dye-cored polylysine dendrimer as luminescent nanoplatform for imaging-guided anticancer drug delivery.

Dendrimers have numerous applications in imaging and drug delivery. Designing a dendrimer diagnostic platform with a well-defined structure and controlled drug delivery is a formidable challenge. Here, we design dendritic polymer-platinum conjugates (G5-PEG-Pt) as pH-responsive nanovesicles for imaging-guided platinum drug delivery. The G5-PEG-Pt have a well-defined structure, intrinsically bright fluorescence, and acid-responsive drug release. The pH-responsive G5-PEG-Pt could rapidly release the platinum drug at acidic pH (5.0) than neutral pH (7.4). The G5-PEG-Pt could enter SKOV-3 human ovarian cancer cells by the endocytosis pathway and exhibited comparative cytotoxicity to free cisplatin. By virtue of the prolonged blood circulation time and the enhanced permeability and retention (EPR) effect, a 4.4-fold higher tumor platinum uptake than that of free cisplatin was achieved, potentially enhancing the therapeutic indexes of the platinum drug. Therefore, these pH-responsive platinum and fluorescent dendrimer conjugates are expected to be potent in vivo cancer optical imaging and therapy platforms.

Acidity/carbon dioxide-sensitive triblock polymer-grafted photoactivated vesicles for programmed release of chemotherapeutic drugs against glioblastoma.

Controllable release of chemotherapeutic drugs in tumor sites remains a big challenge for precision therapy. Herein, we developed acidity/carbon dioxide (H+/CO2)-sensitive poly (ethylene glycol)-b-poly (2-(diisopropylamino) ethyl methacrylate)-b-polystyrene triblock polymer (PEG-b-PDPA-b-PS) grafted photoactivated vesicles for programmed release of chemotherapeutic drugs against glioblastoma. In brief, gold nanoparticles (GNPs) were firstly tethered with the H+/CO2-sensitive PEG-b-PDPA-b-PS polymer. Next, the CO2 precursor (ammonium bicarbonate, NH4HCO3) and doxorubicin (DOX) were loaded during self-assembly process of PEG-b-PDPA-b-PS-tethered GNPs, thus obtaining the multifunctional gold vesicles (denoted as GVND). The programmed multi-stimuli responsive drug release by GVND was undergone in multiple steps as follows: 1) the vesicular architecture of GVND was first swelled in tumor acidic microenvironment, 2) the GVND were partially broken under near-infrared (NIR) laser irradiation, 3) the mild hyperthermia generated by GV triggered the thermal decomposition of encapsulated NH4HCO3, leading to the in situ generation of CO2, 4) the generated CO2 reacted with PDPA of PEG-b-PDPA-b-PS, changing the hydrophilicity and hydrophobicity of GVND, thus vastly breaking its vesicular architecture, finally resulting in a "bomb-like" release of DOX in tumor tissues. Such a multi-stimuli responsive programmed drug delivery and mild hyperthermia under NIR laser activation displayed strong antitumor efficacy and completely eradicated U87MG glioblastoma tumor. This work presented a promising strategy to realize precision drug delivery for chemotherapy against glioblastoma. STATEMENT OF SIGNIFICANCE.

Iridium Tungstate Nanozyme-Mediated Hypoxic Regulation and Anti-inflammation for Duplex Imaging Guided Photothermal Therapy of Metastatic Breast Tumors.

Metastasis of breast cancer is key to poor prognosis and high mortality. However, the excess reactive oxygen species (ROS) and inflammatory response induced by photothermal therapy (PTT) further aggravate tumor metastasis. Meanwhile, the hypoxic tumor microenvironment promotes tumor cells to metastasize to distant organs. Herein, the intrinsic limitations of PTT for metastatic tumor have been addressed by fabricating polyethylene glycol modified iridium tungstate (IrWOx-PEG) nanoparticles. The as-designed IrWOx-PEG nanoparticles displayed good photothermal (PT) conversion ability for duplex photoacoustic/PT imaging guided PTT and multienzyme mimetic feature for broad-spectrum ROS scavenging. On the one hand, IrWOx-PEG effectively removed excess ROS generated during PTT and reduced inflammation. On the other hand, owing to the catalase-like activity, it preferentially triggered the catalytic production of oxygen by decomposing ROS, leading to relieving of the hypoxic microenvironment. Hence, under bimodal imaging guidance, IrWOx-PEG induced PTT completely eliminated in situ breast cancer in 4T1 tumor-bearing mice with no observable system toxicity, as well as further restricting tumor metastasis to other vital organs (lungs) by ROS scavenging, anti-inflammation, and regulating hypoxic microenvironment. We anticipate that this work will lead to new treatment strategies for other metastatic cancers.

Synthetic biology-instructed transdermal microneedle patch for traceable photodynamic therapy.

5-Aminolevulinic acid-based photodynamic therapy heavily depends on the biological transformation efficiency of 5-aminolevulinic acid to protoporphyrin IX, while the lack of an effective delivery system and imaging navigation are major hurdles in improving the accumulation of protoporphyrin IX and optimizing therapeutic parameters. Herein, we leverage a synthetic biology approach to construct a transdermal theranostic microneedle patch integrated with 5-aminolevulinic acid and catalase co-loaded tumor acidity-responsive copper-doped calcium phosphate nanoparticles for efficient 5-aminolevulinic acid-based photodynamic therapy by maximizing the enrichment of intratumoral protoporphyrin IX. We show that continuous oxygen generation by catalase in vivo reverses tumor hypoxia, enhances protoporphyrin IX accumulation by blocking protoporphyrin IX efflux (downregulating hypoxia-inducible factor-1α and ferrochelatase) and upregulates protoporphyrin IX biosynthesis (providing exogenous 5-aminolevulinic acid and upregulating ALA-synthetase). In vivo fluorescence/photoacoustic duplex imaging can monitor intratumoral oxygen saturation and protoporphyrin IX metabolic kinetics simultaneously. This approach thus facilitates the optimization of therapeutic parameters for different cancers to realize Ca2+/Cu2+-interferences-enhanced repeatable photodynamic therapy, making this theranostic patch promising for clinical practice.

A Microneedle Patch with Self-Oxygenation and Glutathione Depletion for Repeatable Photodynamic Therapy.

Photodynamic therapy (PDT) has attained extensive attention as a noninvasive tumor treatment modality. However, the hypoxia in solid tumors, skin phototoxicity of "always on" photosensitizers (PSs), and abundant supply of glutathione (GSH) in cancer cells severely hampered the clinical applications of PDT. Herein, a self-oxygenation nanoplatform (denoted as CZCH) with GSH depletion ability was encapsulated into the hyaluronic acid microneedle patch (MN-CZCH) to simultaneously improve the biosafety and therapeutic efficacy of PDT. The Cu2+-doped porous zeolitic imidazolate framework incorporated with catalase (CAT) is capable of efficiently loading PS 2-(1-hexyloxyethyl)-2-divinylpyropheophorbic-a (HPPH). The CZCH intermingled MN patch (MN-CZCH) could effectively penetrate the stratum corneum, topically transport HPPH to the target tumor site, achieve a long tumor retention time, and enhance the efficacy of PDT via the simultaneously synergistic effect of CAT-catalyzed self-supplying O2 and Cu2+-mediated GSH depletion. Using traceable fluorescence (FL) imaging of the released HPPH from CZCH, the FL imaging-guided repeatable PDT can be achieved for enhanced antitumor efficacy. As a result, the MN-CZCH patch exhibited excellent therapeutic efficacy against melanoma with minimal toxicity, which has promising potential for cancer theranostics.

Multiscale Hierarchical Architecture-Based Bioactive Scaffolds for Versatile Tissue Engineering.

Artificial construction from tendon to bone remains a formidable challenge in tissue engineering owing to their structural complexity. In this work, bioinspired calcium silicate nanowires and alginate composite hydrogels are utilized as building blocks to construct multiscale hierarchical bioactive scaffolds for versatile tissue engineering from tendon to bone. By integrating 3D printing technology and mechanical stretch post-treatment in a confined condition, the obtained composite hydrogels possess bioinspired reinforcement architectures from nano- to submicron- to microscale with significantly enhanced mechanical properties. The biochemical and topographical cues of the composite hydrogel scaffolds provide much more efficient microenvironment to the rabbit bone mesenchymal stem cells and rabbit tendon stem cells, leading to ordered alignment and improved differentiation. The composite hydrogels markedly promote in vivo tissue regeneration from bone to tendon, especially fibrocartilage transitional tissue. Therefore, such calcium silicate nanowires/alginate composite hydrogels with multiscale hierarchical structures have potential application for tissue regeneration from tendon to bone. This work provides an innovative strategy to construct multiscale hierarchical architecture-based scaffolds for tendon/bone engineering.

A "Self-Checking" pH/Viscosity-Activatable NIR-II Molecule for Real-Time Evaluation of Photothermal Therapy Efficacy.

We present a second near-infrared (NIR-II) self-checking molecule, LET-1052, for acidic tumor microenvironment (TME) turn-on photothermal therapy (PTT), followed by viscosity based therapeutic efficacy evaluation by itself in two independent channels, denoted as "self-checking" strategy. In acidic TME, LET-1052 was protonated and turned on NIR-II absorption for PTT under 1064 nm laser irradiation. Subsequently, PTT-induced cellular death increases intracellular viscosity, which inhibited the intramolecular rotation of LET-1052, resulting in the enhancement of NIR-I fluorescence for real-time evaluation of PTT efficacy. After PTT of tumor-bearing mice for different periods of NIR-II laser irradiation, NIR-I fluorescence in the tumor region showed positive correlation with tumor growth inhibition rate, demonstrating reliable and prompt prediction of PTT efficacy. The strategy may be expanded for instant evaluation of other therapeutic modalities for personalized medicine.

Bioactive NIR-II Light-Responsive Shape Memory Composite Based on Cuprorivaite Nanosheets for Endometrial Regeneration.

Intrauterine adhesions (IUAs) caused by mechanical damage or infection increase the risk of infertility in women. Although numerous physical barriers such as balloon or hydrogel are developed for the prevention of IUAs, the therapeutic efficacy is barely satisfactory due to limited endometrial healing, which may lead to recurrence. Herein, a second near-infrared (NIR-II) light-responsive shape memory composite based on the combination of cuprorivaite (CaCuSi4 O10 ) nanosheets (CUP NSs) as photothermal conversion agents and polymer poly(d,l-lactide-co-trimethylene carbonate) (PT) as shape memory building blocks is developed. The as-prepared CUP/PT composite possesses excellent shape memory performance under NIR-II light, and the improved operational feasibility as an antiadhesion barrier for the treatment of IUAs. Moreover, the released ions (Cu, Si) can stimulate the endometrial regeneration due to the angiogenic bioactivity. This study provides a new strategy to prevent IUA and restore the injured endometrium relied on shape memory composite with enhanced tissues reconstruction ability.

Plasmon-Accelerated Generation of Singlet Oxygen on an Au/MoS2 Nanohybrid for Enhanced Photodynamic Killing of Bacterial Pathogens/Cancerous Cells.

Benefiting from its strong cytotoxic features, singlet oxygen (1O2) has garnered considerable research attention in photodynamic therapy (PDT) and thus, plenty of inorganic PDT agents have been recently developed. However, inorganic PDT agents consisting of metal/semiconductor hybrids are surprisingly rare, bearing very low 1O2 quantum yield, and their in vivo PDT applications remain elusive. Herein, we provide an unprecedented report that the Au/MoS2 hybrid under plasmon resonant excitation can sensitize 1O2 generation with a quantum yield of about 0.22, which is much higher than that of the reported hybrid-based photosensitizers (PSs). This significant enhancement in 1O2 quantum yield is attributed to the hot-electron injection from plasmonic AuNPs to MoS2 NSs due to the matched energy levels. Electron paramagnetic resonance (EPR) spectroscopy with spin trapping and spin labeling verifies the plasmonic generation of hot charge carriers and reactive oxygen species such as superoxide and 1O2. This plasmonic PDT agent shows a remarkable photodynamic bacterial inactivation in vitro and anti-cancer therapeutic ability both in vitro and in vivo, which is solely attributed to high 1O2 generation rather than the plasmonic photothermal effect. Hence, plasmonic Au/MoS2 with enhanced 1O2 quantum yield and appreciable in vivo cancer plasmonic PDT performance holds great promise as an inorganic PS to treat near-surface tumors. As a first demonstration of how metal localized surface plasmon resonance could enhance 1O2 generation, the present study opens up promising opportunities for enhancing 1O2 quantum yield of hybrid-based PSs, leading to achieving a high therapeutic index in plasmon PDT.

In-situ TiO2-x decoration of titanium carbide MXene for photo/sono-responsive antitumor theranostics.

BACKGROUND: Sonodynamic therapy (SDT) has emerged as a noninvasive therapeutic modality that involves sonosensitizers and low-intensity ultrasound. However, owing to the rapid recombination of charge carriers, most of the sonosensitizers triggered poor reactive oxygen species (ROS) generation, resulting in unsatisfactory sonodynamic therapeutic effects. RESULTS: Herein, a photo/sono-responsive nanoplatform was developed through the in-situ systhesis of TiO2-x on the surface of two-dimensional MXene (titanium carbide, Ti3C2) for photoacoustic/photothermal bimodal imaging-guided near-infrared II (NIR-II) photothermal enhanced SDT of tumor. Because of several oxygen vacancies and smaller size (~ 10 nm), the in-situ formed TiO2-x nanoparticles possessed narrow band gap (2.65 eV) and high surface area, and thus served as a charge trap to restrict charge recombination under ultrasound (US) activation, resulting in enhanced sonodynamic ROS generation. Moreover, Ti3C2 nanosheets induced extensive localized hyperthermia relieves tumor hypoxia by accelerating intratumoral blood flow and tumor oxygenation, and thus further strengthened the efficacy of SDT. Upon US/NIR-II laser dual-stimuli, Ti3C2@TiO2-x nanoplatform triggered substantial cellular killing in vitro and complete tumor eradication in vivo, without any tumor recurrence and systemic toxicity. CONCLUSION: Our work presents the promising design of photo/sono-responsive nanoplatform for cancer nanotheranostics.

Dye-loaded mesoporous polydopamine nanoparticles for multimodal tumor theranostics with enhanced immunogenic cell death.

BACKGROUND: Tumor phototherapy especially photodynamic therapy (PDT) or photothermal therapy (PTT), has been considered as an attractive strategy to elicit significant immunogenic cell death (ICD) at an optimal tumor retention of PDT/PTT agents. Heptamethine cyanine dye (IR-780), a promising PDT/PTT agent, which can be used for near-infrared (NIR) fluorescence/photoacoustic (PA) imaging guided tumor phototherapy, however, the strong hydrophobicity, short circulation time, and potential toxicity in vivo hinder its biomedical applications. To address this challenge, we developed mesoporous polydopamine nanoparticles (MPDA) with excellent biocompatibility, PTT efficacy, and PA imaging ability, facilitating an efficient loading and protection of hydrophobic IR-780. RESULTS: The IR-780 loaded MPDA (IR-780@MPDA) exhibited high loading capacity of IR-780 (49.7 wt%), good physiological solubility and stability, and reduced toxicity. In vivo NIR fluorescence and PA imaging revealed high tumor accumulation of IR-780@MPDA. Furthermore, the combined PDT/PTT of IR-780@MPDA could induce ICD, triggered immunotherapeutic response to breast tumor by the activation of cytotoxic T cells, resulting in significant suppression of tumor growth in vivo. CONCLUSION: This study demonstrated that the as-developed compact and biocompatible platform could induce combined PDT/PTT and accelerate immune activation via excellent tumor accumulation ability, offering multimodal tumor theranostics with negligible systemic toxicity.

Clinically translatable gold nanozymes with broad spectrum antioxidant and anti-inflammatory activity for alleviating acute kidney injury.

Rationale: Acute kidney injury (AKI) is associated with aberrant generation of oxidative species and inflammation, leading to high mortality of in-hospitalized patients. Although N-acetylcysteine (NAC) showed positive effects in alleviating contrast-induced AKI, the clinical applications are strongly restrained due to the low bioavailability, low renal accumulation, short renal retention time, and high dosage-induced toxicity. Methods: We addressed the clinical dilemma of NAC by developing ultrasmall gold nanoclusters (1-2 nm) capped with NAC (denoted as Au NCs-NAC) as a nanozyme-based antioxidant defense system for AKI alleviation. Rhabdomyolysis-induced AKI mice model was developed, and the same dose of free NAC (as a control) and NAC onto Au NCs (Au NCs-NAC) was used for in vivo investigation of AKI restoration. Results: The as-developed gold nanozyme exhibited high bioavailability and good physicochemical stability as compared to NAC. Meanwhile, Au NCs-NAC showed broad-spectrum antioxidant activity of Au NCs-NAC, offering in vitro renoprotective effects, as well as macrophages by relieving inflammation under hydrogen peroxide or lipopolysaccharide stimulation. Notably, owing to the smaller size than kidney threshold (5.5 nm), Au NCs-NAC displayed preferential renal enrichment (< 2 h) and longer retention (> 24 h) in AKI mice as revealed by fluorescence imaging, thereby largely enhancing the restoration of renal function in AKI mice than free NAC by protecting the kidneys from oxidative injury and inflammation without systemic toxicity, as demonstrated by tissues staining, inflammatory cytokines and biomarkers detection, and mice survival rate. Conclusion: Owing to the synergistic anti-inflammatory/antioxidative effects, and enhanced bioavailability and renal accumulation/retention, Au NCs-NAC displayed far superior therapeutic performance than NAC alone. This work will facilitate the development of high-performance antioxidative nanoplatforms, as well as overcome the clinical limitations of small molecular drugs for AKI treatment and other inflammatory diseases.

Inorganic Nanomaterials with Intrinsic Singlet Oxygen Generation for Photodynamic Therapy.

Inorganic nanomaterials with intrinsic singlet oxygen (1 O2 ) generation capacity, are emerged yet dynamically developing materials as nano-photosensitizers (NPSs) for photodynamic therapy (PDT). Compared to previously reported nanomaterials that have been used as either carriers to load organic PSs or energy donors to excite the attached organic PSs through a Foster resonance energy transfer process, these NPSs possess intrinsic 1 O2 generation capacity with extremely high 1 O2 quantum yield (e.g., 1.56, 1.3, 1.26, and 1.09) than any classical organic PS reported to date, and thus are facilitating to make a revolution in PDT. In this review, the recent advances in the development of various inorganic nanomaterials as NPSs, including metal-based (gold, silver, and tungsten), metal oxide-based (titanium dioxide, tungsten oxide, and bismuth oxyhalide), metal sulfide-based (copper and molybdenum sulfide), carbon-based (graphene, fullerene, and graphitic carbon nitride), phosphorus-based, and others (hybrids and MXenes-based NPSs) are summarized, with an emphasis on the design principle and 1 O2 generation mechanism, and the photodynamic therapeutic performance against different types of cancers. Finally, the current challenges and an outlook of future research are also discussed. This review may provide a comprehensive account capable of explaining recent progress as well as future research of this emerging paradigm.