A Homing Missile-Like Nanotherapeutic with Single-Atom Catalytic Sites for In Situ Elimination of Intracellular Bacterial Pathogens.

Intracellular bacterial pathogens hiding in host cells tolerate the innate immune system and high-dose antibiotics, resulting in recurrent infections that are difficult to treat. Herein, a homing missile-like nanotherapeutic (FeSAs@Sa.M) composed of a single-atom iron nanozyme (FeSAs) core coated with infected macrophage membrane (Sa.M) is developed for in situ elimination of intracellular methicillin-resistant S. aureus (MRSA). Mechanically, the FeSAs@Sa.M initially binds to the extracellular MRSA via the bacterial recognition ability of the Sa.M component. Subsequently, the FeSAs@Sa.M can be transported to the intracellular MRSA-located regions in the host cell like a homing missile under the guidance of the extracellular MRSA to which it is attached, generating highly toxic reactive oxygen species (ROS) for intracellular MRSA killing via the enzymatic activities of the FeSAs core. The FeSAs@Sa.M is far superior to FeSAs in killing intracellular MRSA, proposing a feasible strategy for treating intracellular infections by in situ generating ROS in bacterial residing regions.

Cancer nanomedicine in preoperative therapeutics: Nanotechnology-enabled neoadjuvant chemotherapy, radiotherapy, immunotherapy, and phototherapy.

Surgical resection remains a mainstay in the treatment of malignant solid tumors. However, the use of neoadjuvant treatments, including chemotherapy, radiotherapy, phototherapy, and immunotherapy, either alone or in combination, as a preoperative intervention regimen, have attracted increasing attention in the last decade. Early randomized, controlled trials in some tumor settings have not shown a significant difference between the survival rates in long-term neoadjuvant therapy and adjuvant therapy. However, this has not hampered the increasing use of neoadjuvant treatments in clinical practice, due to its evident downstaging of primary tumors to delineate the surgical margin, tailoring systemic therapy response as a clinical tool to optimize subsequent therapeutic regimens, and decreasing the need for surgery, with its potential for increased morbidity. The recent expansion of nanotechnology-based nanomedicine and related medical technologies provides a new approach to address the current challenges of neoadjuvant therapy for preoperative therapeutics. This review not only summarizes how nanomedicine plays an important role in a range of neoadjuvant therapeutic modalities, but also highlights the potential use of nanomedicine as neoadjuvant therapy in preclinical and clinic settings for tumor management.

NIR-II Light Leveraged Dual Drug Synthesis for Orthotopic Combination Therapy.

Pd-catalyzed bioorthogonal bond cleavage reactions are widely used and frequently reported. It is circumscribed by low reaction efficiency, which may encumber the therapeutic outcome when applied to physiological environments. Herein, an NIR-II light promoted integrated catalyst (CuS@PDA/Pd) (PDA - polydopamine) is designed to accelerate the reaction efficiency and achieve a dual bioorthogonal reaction for combination therapy. As NIR-II light can penetrate deeply into tissue, the Pd-mediated cleavage reaction can be promoted both in vitro and in vivo by the photothermal properties of CuS, beneficial to orthotopic 4T1 tumor treatment. In addition, CuS also catalyzes the synthesis of active resveratrol analogs by the CuAAC reaction. These simultaneously produced anticancer agents result in enhanced antitumor cytotoxicity in comparison to the single treatments. This is a fascinating study to devise an integrated catalyst boosted by NIR-II light for dual bioorthogonal catalysis, which may provide the impetus for efficient bioorthogonal combination therapy in vivo.

NIR-II Hydrogen-Bonded Organic Frameworks (HOFs) Used for Target-Specific Amyloid-ß Photooxygenation in an Alzheimer's Disease Model.

Phototherapy has emerged as a powerful approach for interrupting ß-amyloid (Aß) self-assembly. However, deeper tissue penetration and safer photosensitizers are urgent to be exploited for avoiding damaging nearby normal tissues and improving therapeutic effectiveness. A hydrogen-bonded organic framework (HOF)-based NIR-II photooxygenation catalyst is presented here to settle the abovementioned challenges. By encapsulating the pyridinium hemicyanine dye DSM with a large two-photon absorption (TPA) cross-section in NIR-II window into the porphyrin-based HOF, the resultant DSM@n-HOF-6 exhibits significant two-photon NIR-II-excited Fluorescence Resonance Energy Transfer (FRET) to generate singlet oxygen (1 O2 ) for Aß oxidation. Further, the target peptides of KLVFFAED (KD8) are covalently grafted on DSM@n-HOF-6 to enhance the blood-brain barrier (BBB) permeability and Aß selectivity. The HOF-based photooxygenation catalyst shows an outstanding inhibitory effect of Aß aggregation upon the NIR-II irradiation. Further in vivo studies demonstrate the obvious decrease of craniocerebral Aß plaques and recovery of memory deficits in triple-transgenic AD (3×Tg-AD) model mice.

Targeting RNA G-Quadruplex in SARS-CoV-2: A Promising Therapeutic Target for COVID-19?

The COVID-19 pandemic caused by SARS-CoV-2 has become a global threat. Understanding the underlying mechanisms and developing innovative treatments are extremely urgent. G-quadruplexes (G4s) are important noncanonical nucleic acid structures with distinct biofunctions. Four putative G4-forming sequences (PQSs) in the SARS-CoV-2 genome were studied. One of them (RG-1), which locates in the coding sequence region of SARS-CoV-2 nucleocapsid phosphoprotein (N), has been verified to form a stable RNA G4 structure in live cells. G4-specific compounds, such as PDP (pyridostatin derivative), can stabilize RG-1 G4 and significantly reduce the protein levels of SARS-CoV-2 N by inhibiting its translation both in vitro and in vivo. This result is the first evidence that PQSs in SARS-CoV-2 can form G4 structures in live cells, and that their biofunctions can be regulated by a G4-specific stabilizer. This finding will provide new insights into developing novel antiviral drugs against COVID-19.

Self-Propelled Active Photothermal Nanoswimmer for Deep-Layered Elimination of Biofilm In Vivo.

Increasing penetration of antibacterial agents into biofilm is a promising strategy for improvement of therapeutic effect and slowdown of the progression of antibiotic resistance. Herein, we design a near-infrared (NIR) light-driven nanoswimmer (HSMV). Under NIR light irradiation, HSMV performs efficient self-propulsion and penetrates into the biofilm within 5 min due to photothermal conversion of asymmetrically distributed AuNPs. The localized thermal (∼45 °C) and thermal-triggered release of vancomycin (Van) leads to an efficient combination of photothermal therapy and chemotherapy in one system. The active motion of HSMV increases the effective distance of photothermal therapy (PTT) and also improves the therapeutic index of the antibiotic, resulting in superior biofilm removal rate (>90%) in vitro. Notably, HSMV can eliminate S. aureus biofilms grown in vivo under 10 min of laser irradiation without damage to healthy tissues. This work may shed light on therapeutic strategies for in vivo treatment of biofilm-associated infections.

A Biocompatible Second Near-Infrared Nanozyme for Spatiotemporal and Non-Invasive Attenuation of Amyloid Deposition through Scalp and Skull.

Phototherapy, such as photodynamic therapy and photothermal therapy, holds great potential for modulation of Alzheimer's ß-amyloid (Aß) self-assembly. Unfortunately, current works for phototherapy of Alzheimer's disease (AD) are just employing either visible or first near-infrared (NIR-I) light with limited tissue penetration, which can not avoid damaging nearby normal tissues of AD patients through the dense skull and scalp. To overcome the shortcomings of AD phototherapy, herein we report an amyloid targeting, N-doped three-dimensional mesoporous carbon nanosphere (KD8@N-MCNs) as a second near-infrared (NIR-II) PTT agent. This makes it possible for photothermal dissociation of Aß aggregates through the scalp and skull in a NIR-II window without hurting nearby normal tissues. Besides, KD8@N-MCNs have both superoxide dismutase and catalase activities, which can scavenge intracellular superfluous reactive oxygen species and alleviate neuroinflammation in vivo. Furthermore, KD8@N-MCNs efficiently cross the blood-brain barrier owing to the covalently grafted target peptides of KLVFFAED on the nanosphere surface. In vivo studies demonstrate that KD8@N-MCNs decrease Aß deposits, ameliorate memory deficits, and alleviate neuroinflammation in the 3xTg-AD mouse model. Our work provides a biocompatible and non-invasive way to attenuate AD-associated pathology.

Near-Infrared Activated Black Phosphorus as a Nontoxic Photo-Oxidant for Alzheimer's Amyloid-ß Peptide.

The inhibition of amyloid-ß (Aß) aggregation by photo-oxygenation has become an effective way of treating Alzheimer's disease (AD). New near-infrared (NIR) activated treatment agents, which not only possess high photo-oxygenation efficiency, but also show low biotoxicity, are urgently needed. Herein, for the first time, it is demonstrated that NIR activated black phosphorus (BP) could serve as an effective nontoxic photo-oxidant for amyloid-ß peptide in vitro and in vivo. The nanoplatform BP@BTA (BTA: one of thioflavin-T derivatives) possesses high affinity to the Aß peptide due to specific amyloid selectivity of BTA. Importantly, under NIR light, BP@BTA can significantly generate a high quantum yield of singlet oxygen (1 O2 ) to oxygenate Aß, thereby resulting in inhibiting the aggregation and attenuating Aß-induced cytotoxicity. In addition, BP could finally degrade into nontoxic phosphate, which guarantees the biosafety. Using transgenic Caenorhabditis elegans CL2006 as AD model, the results demonstrate that the 1 O2 -generation system could dramatically promote life-span extension of CL2006 strain by decreasing the neurotoxicity of Aß.

Chirality-Selected Chemical Modulation of Amyloid Aggregation.

Due to the composed α-helical/ß-strand structures, ß-amyloid peptide (Aß) is sensitive to chiral environments. The orientation and chirality of the Aß strand strongly influence its aggregation. Aß-formed fibrils have a cascade of chirality. Therefore, for selectively targeting amyloid aggregates, chirality preference can be one key issue. Inspired by the natural stereoselectivity and the ß-sheet structure, herein, we synthesized a series of d- and l-amino acid-modified polyoxometalate (POM) derivatives, including positively charged amino acids (d-His and l-His) and negatively charged (d-Glu and l-Glu) and hydrophobic amino acids (d-Leu, l-Leu, d-Phe, and l-Phe), to modulate Aß aggregation. Intriguingly, Phe-modified POMs showed a stronger inhibition effect than other amino acid-modified POMs, as evidenced by multiple biophysical and spectral assays, including fluorescence, circular dichroism, NMR, molecular dynamic simulations, and isothermal titration calorimetry. More importantly, d-Phe-modified POM had an 8-fold stronger inhibition effect than l-Phe-modified POM, indicating high enantioselectivity. Furthermore, in vivo studies demonstrated that the chiral POM derivatives crossed the blood-brain barrier, extended the life span of AD transgenic Caenorhabditis elegans CL2006 strain, and had low cytotoxicity, even at a high dosage.

Redox-Activated Near-Infrared-Responsive Polyoxometalates Used for Photothermal Treatment of Alzheimer's Disease.

Adjustable structure, excellent physiochemical properties, and good biocompatibility render polyoxometalates (POMs) as a suitable drug agent for the treatment of Alzheimer's disease (AD). However, previous works using POMs against AD just focus on the inhibition of amyloid-ß (Aß) monomer aggregation. In consideration that both Aß fibrils and reactive oxygen species (ROS) are closely associated with clinical development of AD symptoms, it would be more effective if POMs can disaggregate Aß fibrils and eliminate ROS as well. Herein, a redox-activated near-infrared (NIR) responsive POMs-based nanoplaform (rPOMs@MSNs@copolymer) is developed with high photothermal effect and antioxidant activity. The rPOMs@MSNs@copolymer can generate local hyperthermia to disaggregate Aß fibrils under NIR laser irradiation because of POMs (rPOMs) with strong NIR absorption. Furthermore, Aß-induced ROS can be scavenged by the antioxidant activity of rPOMs. To the authors' knowledge, there is no report of using rPOMs for NIR photothermal treatment of AD. This work may promote the development of multifunctional inorganic agents for biomedical applications.

Using Multifunctional Peptide Conjugated Au Nanorods for Monitoring ß-amyloid Aggregation and Chemo-Photothermal Treatment of Alzheimer's Disease.

Development of sensitive detectors of Aß aggregates and effective inhibitors of Aß aggregation are of diagnostic importance and therapeutic implications for Alzheimer's disease (AD) treatment. Herein, a novel strategy has been presented by self-assembly of peptide conjugated Au nanorods (AuP) as multifunctional Aß fibrillization detectors and inhibitors. Our design combines the unique high NIR absorption property of AuNRs with two known Aß inhibitors, Aß15-20 and polyoxometalates (POMs). The synthesized AuP can effectively inhibit Aß aggregation and dissociate amyloid deposits with NIR irradiation both in buffer and in mice cerebrospinal fluid (CSF), and protect cells from Aß-related toxicity upon NIR irradiation. In addition, with the shape and size-dependent optical properties, the nanorods can also act as effective diagnostic probes to sensitively detect the Aß aggregates. This is the first report to integrate 3 segments, an Aß-targeting element, a reporter and inhibitors, in one drug delivery system for AD treatment.

A NIR-controlled cage mimicking system for hydrophobic drug mediated cancer therapy.

Most chemotherapeutic drugs commonly suffer from several shortcomings, including the lack of aqueous solubility, limited stability and adverse side effects. Although caging strategy has recently been employed as an effective approach to conceal and stabilize these drugs to achieve light-activated cancer therapy, it is plagued by the sophisticated drug modification process and deleterious solvent usage. In addition, using UV or Visible light to remove photocaged group is restricted to its limited tissue penetration ability in and phototoxicity. In this paper, by anchoring photochromic spiropyran on the mesoporous silica coated upconversion nanoparticles (UCNP-SP), we design a NIR-controlled cage mimicking system. Our results indicate that hydrophobic drug can be concealed inside the channels of the nanocarrier with high stability and "uncaged" via NIR irradiation-triggered hydrophobicity-hydrophilicity switch of the spiropyran molecules, finally inducing drug release and recovering their bioactivity. Moreover, under NIR illumination, the UV/Visible emissions from UCNP can also efficaciously initiate the generation of reactive oxygen species (ROS) by Curcumin, further improving the therapeutic efficiency. Both in vitro and in vivo experimental results validate that NIR irradiated nanosystem can produce remarkably enhanced antitumor efficiency.

A GO-Se nanocomposite as an antioxidant nanozyme for cytoprotection.

GO-Se nanocomposites are fabricated with excellent glutathione peroxidase (GPx)-like properties to protect cells against oxidative stress. Compared with SeNPs, the GO-Se nanozymes exhibit higher GPx-mimic catalytic efficiency. Cell experiments further confirm their excellent cytoprotection capacity.

Metal-organic-framework-supported immunostimulatory oligonucleotides for enhanced immune response and imaging.

We have demonstrated the ability of iron carboxylate metal-organic frameworks to efficiently deliver unmethylated cytosine-phosphate-guanine oligonucleotides. The nanoconjugates induced a stronger immune response than did free cytosine-phosphateguanine oligonucleotides and showed T2-magnetic resonance imaging ability both in vitro and in vivo.

A multifunctional upconverting nanoparticle incorporated polycationic hydrogel for near-infrared triggered and synergistic treatment of drug-resistant bacteria.

Recently, antibiotic drug-resistant therapies have become very important due to the emergence of antibiotic-resistant bacterial strains. The development of novel antibacterial materials has received significant attention. Here, quaternized chitosan hydrogels incorporated with NaYF4:Er/Yb/Mn@photosensitizer-doped silica (UCNPs/MB) were synthesized for effective killing of both gram-positive oxacillin-resistant S. aureus (DR-S. aureus) and gram-negative kanamyclin-resistant E. coli (DR-E. coli) bacteria upon near-infrared (NIR) laser irradiation. In this system, the cationic macroporous nature of the hydrogel acts as a molecular 'anion sponge', which sucks the outer part of the anionic microbe membrane into the gel interior voids and causes microbe membrane disruption. By incorporating UCNPs/MB-doped silica into the hydrogel, we have combined photodynamic therapy (PDT) with quaternized chitosan to obtain a high therapeutic index via a synergistic effect. In vitro experiments have demonstrated that our system had excellent antibacterial efficiency to both DR-S. aureus and DR-E. coli bacteria. More importantly, our new synergistic treatment modality provided an excellent therapy platform for drug-resistant bacteria, which could improve antimicrobial efficiency.

Using Plasmonic Copper Sulfide Nanocrystals as Smart Light-Driven Sterilants.

As an efficient route to control pet overpopulation and develop neutered experimental animals, male sterilization via surgical techniques, chemical injections, and antifertility vaccines has brought particular attention recently. However, these traditional ways usually induce long-term adverse reactions, immune suppression, and serious infection and pain. To overcome the above limitations, we developed a platform in the present study by using plasmonic copper sulfide nanocrystals (Cu2-xS NCs) as intelligent light-driven sterilants with ideal outcomes. Upon NIR laser irradiation, these well-prepared Cu2-xS NCs can possess NIR-induced hyperthermia and generate high levels of reactive oxygen species (ROS). Due to the cooperation of photothermal and photodynamic effects, these nanocrystals exhibited NIR-mediated toxicity toward Sertoli cells both in vitro and in vivo in a mild manner. We attribute the potential mechanism of cellular injury to the apoptosis-related death and denaturation of protein in the testicles. Furthermore, the possible metabolism route and long-term toxicity of these nanocrystals after testicular injection indicate their high biocompatibility. Taking together, our study on the NIR-induced toxicity of Cu2-xS NCs provides keen insights for the usage of plasmonic nanomaterials in biomedicine.

Single-layer tungsten oxide as intelligent photo-responsive nanoagents for permanent male sterilization.

Permanent male sterilization has been recognized as useful tools for the development of neuter experimental animals and fattening livestock, as well as efficient control of pet overpopulation. Traditional routes such as surgical ways, chemical injections, and anti-fertility vaccines have addressed these crucial problems with idea outcomes. However, these routes usually bring out serious pain and infection towards animals, as well as induce long-term adverse reaction and immune suppression. Thus, a convenient, but non-surgical strategy for male sterilization under a mild manner is highly desirable. Here, for the first time, we demonstrate a novel platform for male sterilization by using single-layer WO2.72 nanosheets as smart photo-responsive sterilants. Upon a 980 nm irradiation, these nanoagents can possess intrinsic NIR-induced hyperthermia and sensitize the formation of singlet oxygen due to the cooperation of photothermal and photodynamic effects. Mechanism of cellular injury can be attributed to the denaturation of protein and apoptosis-related death. Moreover, long-term toxicity and possible metabolism route after testicular injection are discussed, indicating the neglectable systemic toxicity and high bio-compatibility of our nanoagents. Overall, our strategy can extremely overcome the shortcomings in various routine routes and suggest the new biological application of nanomaterials.

An efficient nano-based theranostic system for multi-modal imaging-guided photothermal sterilization in gastrointestinal tract.

Since understanding the healthy status of gastrointestinal tract (GI tract) is of vital importance, clinical implementation for GI tract-related disease have attracted much more attention along with the rapid development of modern medicine. Here, a multifunctional theranostic system combining X-rays/CT/photothermal/photoacoustic mapping of GI tract and imaging-guided photothermal anti-bacterial treatment is designed and constructed. PEGylated W18O49 nanosheets (PEG-W18O49) are created via a facile solvothermal method and an in situ probe-sonication approach. In terms of excellent colloidal stability, low cytotoxicity, and neglectable hemolysis of PEG-W18O49, we demonstrate the first example of high-performance four-modal imaging of GI tract by using these nanosheets as contrast agents. More importantly, due to their intrinsic absorption of NIR light, glutaraldehyde-modified PEG-W18O49 are successfully applied as fault-free targeted photothermal agents for imaging-guided killing of bacteria on a mouse infection model. Critical to pre-clinical and clinical prospects, long-term toxicity is further investigated after oral administration of these theranostic agents. These kinds of tungsten-based nanomaterials exhibit great potential as multi-modal contrast agents for directed visualization of GI tract and anti-bacterial agents for phothothermal sterilization.

Immunostimulatory oligonucleotides-loaded cationic graphene oxide with photothermally enhanced immunogenicity for photothermal/immune cancer therapy.

Graphene oxide (GO) has attracted tremendous research interest due to its excellent electrical, thermal, and mechanical properties. Here, we apply the polyethylene glycol (PEG) and polyethylenimine (PEI) dual-polymer-functionalized GO (GO-PEG-PEI) as the carrier for efficient CpG delivery. GO-PEG-PEI can significantly promote the production of proinflammatory cytokines and enhance the immunostimulatory effect of CpG. In addition, the NIR optical absorbance of GO-PEG-PEI has been further applied to control the immunostimulatory activity of CpG ODNs, showing remarkably enhanced immunostimulation responses under NIR laser irradiation, owing to the photothermally induced local heating that accelerated intracellular trafficking of nanovectors. This is the first demonstration of using the photothermally enhanced intracellular transportation of nanocarriers for light-controllable CpG delivery. In vivo assay demonstrates that the GO-PEG-PEI-CpG complex provides synergistic photothermal and immunological effects under laser irradiation for cancer treatment, which shows the highest efficiency in tumor reduction, implying the excellent therapeutic efficacy of the GO-PEG-PEI-CpG complex in cancer therapy.

A multi-stimuli responsive gold nanocage-hyaluronic platform for targeted photothermal and chemotherapy.

Noninvasive and pinpointed intracellular drug release that responds to multiple stimulus is still a formidable challenge for cancer therapy. Herein, we reported a multi-stimuli responsive platform based on drug loaded gold nanocages @ hyaluronic acid (AuNCs-HA) for pinpointed intracellular drug release. These well-prepared nanohybrids could specifically recognize cancer cells via HA-CD44 interactions and be efficiently endocytosed by receptor-mediated process. Subsequently, the coated HA molecules could be degraded in lysosomes, resulting in the release of encapsulated drug. In addition, by taking advantage of the excellent photothermal properties, the AuNCs could accelerate the release of encapsulated drug and induce a higher therapeutic efficacy upon near-infrared (NIR) irradiation. In vitro results confirmed that the encapsulated drug could only be pinpointedly released in intracellular environments, which permitted high therapeutic efficacy against cancer cells and minimized the side effects. Importantly, as compared to that of the two therapies independently, a complete inhibition of tumor growth treated with the combination of chemotherapy and photothermal therapy was observed in vivo. Taken together, our present study provides new insights into developing pinpointed, multi-stimuli responsive intracellular drug release systems for synergistic cancer therapy.