Developing the second near-infrared (NIR-II) photoacoustic (PA) agent is of great interest in bioimaging. Ag2Se quantum dots (QDs) are one kind of potential probe for applications in NIR-II photoacoustic imaging (PAI). However, the surfaces with excess anions of Ag2Se QDs, which increase the probability of nonradiative transitions of excitons benefiting PA imaging, are not conducive to binding electron donor ligands for potential biolabeling and imaging. In this study, Staphylococcus aureus (S. aureus) cells are driven for the biosynthesis of Ag2Se QDs with catalase (CAT). Biosynthesized Ag2Se (bio-Ag2Se-CAT) QDs are produced in Se-enriched environment of S. aureus and have a high Se-rich surface. The photothermal conversion efficiency of bio-Ag2Se-CAT QDs at 808 and 1064 nm is calculated as 75.3% and 51.7%, respectively. Additionally, the PA signal responsiveness of bio-Ag2Se-CAT QDs is ≈10 times that of the commercial PA contrast agent indocyanine green. In particular, the bacterial CAT is naturally attached to bio-Ag2Se-CAT QDs surface, which can effectively relieve tumor hypoxia. The bio-Ag2Se-CAT QDs can relieve heat-initiated oxidative stress while undergoing effective photothermal therapy (PTT). Such biosynthesis method of NIR-II bio-Ag2Se-CAT QDs opens a new avenue for developing multifunctional nanomaterials, showing great promise for PAI, hypoxia alleviation, and PTT.

Accurate visualization of tumor microenvironment is of great significance for personalized medicine. Here, we develop a near-infrared (NIR) fluorescence/photoacoustic (FL/PA) dual-mode molecular probe (denoted as NIR-CE) for distinguishing tumors based on carboxylesterase (CE) level by an analyte-induced molecular transformation (AIMT) strategy. The recognition moiety for CE activity is the acetyl unit of NIR-CE, generating the pre-product, NIR-CE-OH, which undergoes spontaneous hydrogen atom exchange between the nitrogen atoms in the indole group and the phenol hydroxyl group, eventually transforming into NIR-CE-H. In cellular experiments and in vivo blind studies, the human hepatoma cells and tumors with high level of CE were successfully distinguished by both NIR FL and PA imaging. Our findings provide a new molecular imaging strategy for personalized treatment guidance.

Photoacoustic imaging (PAI) in the second near-infrared region (NIR-II), due to deeper tissue penetration and a lower background interference, has attracted widespread concern. However, the development of NIR-II nanoprobes with a large molar extinction coefficient and a high photothermal conversion efficiency (PCE) for PAI and photothermal therapy (PTT) is still a big challenge. In this work, the NIR-II CuTe nanorods (NRs) with large molar extinction coefficients ((1.31 +/- 0.01) x 10(8) cm(-1)M-1 at 808 nm, (7.00 +/- 0.38) x 10(7) cm(-1)M-1 at 1064 nm) and high PCEs (70% at 808 nm, 48% at 1064 nm) were synthesized by living Staphylococcus aureus (S. aureus) cells as biosynthesis factories. Due to the strong light-absorbing and high photothermal conversion ability, the in vitro PA signals of CuTe NRs were about 6 times that of indocyanine green (ICG) in both NIR-I and NIR-II. In addition, CuTe NRs could effectively inhibit tumor growth through PTT. This work provides a new strategy for developing NIR-II probes with large molar extinction coefficients and high PCEs for NIR-II PAI and PTT.

Lactate-enriched tumor microenvironment (TME) fosters an immunosuppressive milieu to hamper the functionality of tumor-associated macrophages (TAMs). However, tackling the immunosuppressive effects wrought by lactate accumulation is still a big challenge. Herein, we construct a dual enzyme-driven cascade reaction platform (ILH) with immunosuppressive TME modulation for photoacoustic (PA) imaging-guided catalytic therapy and immune activation. The ILH is composed of iridium (Ir) metallene nanozyme, lactate oxidase (LOx), and hyaluronic acid (HA). The combination of Ir nanozyme and LOx can not only efficiently consume lactate to reverse the immunosuppressive TME into an immunoreactive one by promoting the polarization of TAMs from the M2 to M1 phenotype, thus enhancing antitumor defense, but also alleviate tumor hypoxia as well as induce strong oxidative stress, thus triggering immunogenic cell death (ICD) and activating antitumor immunity. Furthermore, the photothermal performance of Ir nanozyme can strengthen the cascade catalytic ability and endow ILH with a PA response. Based on the changes in PA signals from endogenous molecules, three-dimensional multispectral PA imaging was utilized to track the process of cascade catalytic therapy in vivo. This work provides a nanoplatform for dual enzyme-driven cascade catalytic therapy and immune activation by regulating the immunosuppressive TME.

Controllable release of chemotherapeutic drugs in tumor sites remains a big challenge for precision ther-apy. 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 pho-toactivated 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 mi-croenvironment, 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, lead-ing to the in situ generation of CO2, 4) the generated CO2 reacted with PDPA of PEG-b-PDPA-b-PS, chang-ing 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 center dot An acidity/carbon dioxide-sensitive triblock polymer is synthesized.center dot Multi-stimuli responsive gold vesicles (GVND) co-loaded with ammonium bicarbonate (NH4HCO3) and doxorubicin (DOX) are prepared.center dot The GVND are progressively responsive to tumor acidic microenvironment, light irradiation, and the in situ generated CO2.center dot The GVND have the potential to be used for multi-stimuli responsive programmed release of DOX against glioblastoma.(c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Diabetes mellitus, an epidemic with a rapidly increasing number of patients, always leads to delayed wound healing associated with consistent pro-inflammatory M1 polarization, decreased angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Herein, a poly (lactic-co-glycolic acid) (PLGA)-based microneedle patch loaded with magnesium hydride (MgH2) (MN-MgH2) is manufactured for defeating diabetic wounds. The application of microneedle patch contributes to the transdermal delivery and the prolonged release of MgH2 that can generate hydrogen (H2) and magnesium ions (Mg2+) after reaction with body fluids. The released H2 reduces the production of ROS, transforming the pathological microenvironment induced by diabetes mellitus. Meanwhile, the released Mg2+ promotes the polarization of pro-healing M2 macrophages. Consequently, cell proliferation and migration are improved, and angiogenesis and tissue regeneration are enhanced. Such intelligent microneedle patch provides a novel way for accelerating wound healing through steadily preserving and releasing of H2 and Mg2+ locally and sustainably.

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.

Gas therapy has emerged as a promising "green" treatment modality for malignant cancer, however, the targeted delivery of gas donors as well as the controlled gas release remain a formidable challenge. Herein, self-assembled gold nanovesicles (GVs) loaded with ammonium sulfide ((NH4)(2)S) (denoted as GV-(NH4)(2)S) were developed as theranostic nanoplatform for near-infrared (NIR)-activated in-situ hydrogen sulfide (H2S) generation, controllable gas delivery, and combined photothermal/gas therapy of cancer. GVs had the following features, (1) large hollow cavity, offering high encapsulation efficiency of (NH4)(2)S (similar to 95%), (2) strong plasmon coupling effect, promoting high photothermal effect under NIR laser irradiation. Upon laser irradiation, GVs were ruptured, thus allowing the simultaneous release and decomposition of (NH4)(2)S to generate H2S. The generated H2S induced significant mitochondrial damage and thus reduced adenosine triphosphate (ATP) energy level. Consequently, upon integration, GV-(NH4)(2)S triggered substantial tumor cell killing in vitro and complete 4T1 tumor ablation in vivo, with negligible tumor recurrence and systemic side effects, under the guidance of photoacoustic (PA)/photothermal duplex imaging. This work highlighted the great promise of GVs as a versatile nanocarrier for spatio-temporally controlled and on-demand delivery of gaseous messengers to achieve precision cancer theranostics. (C) 2021 Elsevier Ltd. All rights reserved.

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 TiO 2-x on the surface of two-dimensional MXene (titanium carbide, Ti 3 C 2 ) 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 TiO 2-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, Ti 3 C 2 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, Ti 3 C 2 @TiO 2-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. Graphical Abstract

Acute kidney injury (AKI) is a kind of kidney disease with a high mortality rate, and is predominantly associated with abundant endogenous reactive oxygen/nitrogen species (RONS). However, there are no universal clinical treatment options currently. Development of antioxidants with high kidney enrichment is highly desired to prevent AKI. As a promising new artificial enzyme, nanozymes have attracted extensive attention over the past decade because of their commendable advantages over natural and traditional artificial enzymes. In this study, we reported ultrasmall polyvinylpyrrolidone-coated iridium nanoparticles (denoted as Ir NPs-PVP, 1.5 nm) as multi-enzyme mimetic to scavenge a variety of RONS, offering an efficient RONS-induced cellular protection. Meanwhile, computed tomography and inductively coupled plasma mass spectrometry demonstrated preferential renal uptake of Ir NPs-PVP following intravenous administration, leading to alleviate clinical symptoms in mice subjected to rhabdomyolysis- or cis-platinum-induced AKI. Impressively, ultrasmall Ir NPs-PVP exhibit relatively low systemic side effects in vivo due to rapid renal clearance via urine. Our work presents the clinically translatable potential of ultrasmall nanozymes for AKI management.

Acute kidney injury (AKI) is frequently triggered by abundant reactive oxygen/nitrogen species (RONS) and leads to high morbidity and mortality in clinic. Unfortunately, the current clinical treatment options are only limited to supportive care, and hence, the development of nano-antioxidants with high kidney enrichment is an attractive novel strategy for AKI management. Herein, self-assembled ultrasmall nanodots are reported that consist of iron ion, gallic acid, and polyvinylpyrrolidone (denoted as FGP nanodots) as broad-spectrum RONS scavengers to alleviate both glycerinum- and cis-platinum- induced AKI in mice. Ultrasmall FGP nanodots (≈3.5 nm) offer efficient protection in vitro and reduce cellular apoptosis after H2 O2 stimulation by eliminating various RONS including hydroxyl radical (·OH), superoxide anion (·O2- ), nitric oxide (NO), and peroxynitrite (ONOO- ), etc. In vivo duplex magnetic resonance/fluorescence imaging demonstrates preferential accumulation of FGP nanodots in the kidneys with rapid renal clearance through urine. Importantly, FGP nanodots exhibit remarkable RONS consumption in vivo with enhanced biocompatibility and biodegradability, resulting in superior therapeutic effect than small molecule drug (Amifostine) in two AKI mouse models. This study presents the promising potential of ultrasmall self-assembled FGP nanodots as imaging contrast agent and broad-spectrum antioxidant nanomedicine for AKI theranotics.

[This corrects the article DOI: 10.1016/j.cej.2020.127371.].

Acute kidney injury (AKI) is a common kidney disease with high mortality rate, while surprisingly, the supportive treatment and renal replacement are the only available clinical treatment options to date. The onset of AKI is often triggered by excessive toxic reactive oxygen/nitrogen species (RONS), and hence, the development of antioxidants with high renal accumulation and effective renal clearance is highly demanded to consume RONS in the kidneys. In this study, we developed ultrasmall polyvinylpyrmlidone-coated platinum nanoparticles (Pt NPs-PVP, similar to 3 nm) as multienzyme mimetics (catalase, peroxidase, and superoxide dismutase). Thanks to their excellent PONS scavenging ability, Pt NPs-PVP effectively reduced the hydrogen peroxide induced cellular damage. Analytical (inductively coupled plasma mass spectrometry) as well as imaging (photoacoustic and computed tomography) techniques revealed the preferential renal uptake and high enrichment of ultrasmall Pt NPs-PVP after intravenous administration, offering remarkable relief of the clinical symptoms of glycerol-induced AKI mice without any apparent systemic toxicity in vivo. Importantly, because of their ultrasmall size, Pt NPs-PVP exhibited rapid excretion from healthy mice, presenting relatively low toxicity and side effects. In conclusion, our work demonstrated ultrasmall Pt nanozyme as a state of the art antioxidant for dual-modal imaging guided treatment of AKI with improved treatment efficacy.

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.

Background Acute kidney injury (AKI) with high mortality rates is associated with an excess of reactive oxygen/nitrogen species (RONS) within kidney tissues. Recently, nanomedicine antioxidant therapy has been used to alleviate AKI. Herein, we synthesized ultrasmall Prussian blue nanozymes (PB NZs, 4.5 nm) as theranostic agents for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided AKI treatment. Results PB NZs exhibited multi-enzyme mimetic abilities, promoting the effective elimination of RONS both in vitro and in vivo. Moreover, benefiting from their imaging contrast properties, the rapid renal accumulation of PB NZs was verified by in vivo PA/MR dual-modal imaging. Due to their excellent enrichment in the kidney and unique multi-enzyme mimetic abilities, ultrasmall PB NZs displayed superior AKI treatment efficacy compared with that of amifostine in two clinically relevant types of AKI induced murine models (either by rhabdomyolysis or cisplatin). Conclusion Our findings suggested ultrasmall PB NZs, as nanozyme theranostics, have great potential for AKI management. Graphic abstract

Rhabdomyolysis-induced acute kidney injury (AKI) is closely related to abundant reactive oxygen species (ROS). Owing to the multi-enzymatic activity and broad-spectrum ROS scavenging capacity of ceria nanoparticles (ceria NPs), herein, we report ultrasmall citric acid modified ceria nanozymes (3-4 nm) as antioxidants to alleviate rhabdomyolysis-induced AKI through removing excessive ROS. The as-prepared ceria NPs exhibited multi-enzymatic properties such as peroxidase, catalase, and superoxide dismutase, offering efficient protection of renal cells against H2O2 stimulation in vitro. Moreover, due to their ultrasmall size, ceria NPs could efficiently accumulate in the kidneys, thus protecting renal cells against ROS in vivo. Our results present ultrasmall ceria nanozymes as antioxidants for rhabdomyolysis-induced AKI alleviation, which shows great potential in clinic.

Cobalt carbide-based theranostic agents were developed for magnetic resonance/photoacoustic/photothermal multimodal imaging guided photothermal therapy of cancer.