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Hepatic ischemia-reperfusion injury (IRI) is a common pathological process during hepatectomy and liver transplantation and the two primary reasons for hepatic IRI are reactive oxygen species (ROS)-mediated oxidative stress and excessive inflammatory responses. Herein, a novel antioxidant nanodrug (A-MPDA@Fe 3 O 4 @PVP) is prepared by employing L-arginine-doped mesoporous polydopamine (A-MPDA) nanoparticles as the carrier for deposition of ultra-small ferric oxide (Fe 3 O 4 ) nanoparticles and further surface modification with polyvinylpyrrolidone (PVP). A-MPDA@Fe 3 O 4 @PVP not only effectively reduces the aggregation of ultra-small Fe 3 O 4 , but also simultaneously replicates the catalytic activity of catalase (CAT) and superoxide dismutase (SOD). A-MPDA@Fe 3 O 4 @PVP with good antioxidant activity can rapidly remove various toxic reactive oxygen species (ROS) and effectively regulate macrophage polarization in vitro . In the treatment of hepatic IRI, A-MPDA@Fe 3 O 4 @PVP effectively alleviates ROS-induced oxidative stress, reduces the expression of inflammatory factors, and prevents apoptosis of hepatocytes through immune regulation. A-MPDA@Fe 3 O 4 @PVP can further protect liver tissue by activating the PPARγ/NF-κB pathway. This multiplex antioxidant enzyme therapy can provide new references for the treatment of IRI in organ transplantation and other ROS-related injuries such as fibrosis, cirrhosis, and bacterial and hepatic viral infection.

To inhibit bacterial infection in situ and improve osseointegration are essentially important for long-term survival of an orthopedic implant, in particular for infection-associating revision surgery. Herein, we fabricate a functional molybdenum disulfide (MoS 2 )/polydopamine (PDA)-arginine-glycine-aspartic acid (RGD) coating on titanium (Ti) implant to address above concerns simultaneously. The coating not only improved the osteogenesis of mesenchymal stem cells (MSCs), but also endowed Ti substrates with effective antibacterial ability when exposing to near-infrared (NIR) irradiation. It accelerated glutathione (GSH) oxidation via photothermal energy and induced intrinsic ROS-independent oxidative stress damage deriving from MoS 2 nanosheets. The results displayed that RGD-decorated MoS 2 nanosheets significantly increased the cellular osteogenic behaviors of MSCs via up-regulating osteogenesis-related genes (ALP, Runx2, Col I and OCN) in vitro. Moreover, the functionalized Ti substrates demonstrated great antibacterial efficiency of over 92.6% inhibition for S. aureus and E. coli under NIR-irradiation. Hyperthermia induced by photothermal effect accelerated the GSH consumption and ROS-independent oxidative stress destroyed the integrity of bacteria membranes, which synergistically led to protein leakage and ATP decrease. Furthermore, co-culture experiment showed that S. aureus contamination was efficiently cleaned from MoS 2 /PDA-RGD surface after NIR photothermal treatment, while MSCs adhered and proliferated on the MoS 2 /PDA-RGD surface. In an S. aureus infection model in vivo, MoS 2 /PDA-RGD modified Ti rods killed bacteria with an efficiency of 94.6% under NIR irradiation, without causing damage to normal tissue. More importantly, the MoS 2 /PDA-RGD modified Ti implants accelerated new bone formation in comparison with TNT implants in vivo., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The precise tumor cell-specific delivery of therapeutic proteins and the elimination of side effects associated with routine chemotherapeutic agents are two current critical considerations for tumor therapy. In this study, we report a reactive oxygen species (ROS)-activated yolk-shell nanoplatform for the tumor-specific co-delivery of cytochrome c (Cyt c) prodrug and doxorubicin, in which the bioactivity of Cyt c could be restored by the intracellular ROS-trigger and readily initiate the sequential doxorubicin release. The DOX-loaded lactobionic acid-modified yolk-shell mesoporous silica nanoparticles were first encapsulated with 4-nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl carbonate (NBC)-modified Cyt c via boronic ester linkages, and functionalized again with lactobionic acid to further shield Cyt c and confer the selective tumor targeting against liver cancer cells. The key feature in this design is that by taking advantage of the boronic ester linkage, the cytotoxicity of Cyt c capped on the nanoparticle could be temporarily deactivated during blood transportation and rapidly restored upon exposure to the ROS-rich microenvironment within liver cancer cells, thereby simultaneously achieving the protein therapy and stimuli-responsive doxorubicin release. This study presents a novel strategy for the development of tumor-sensitive co-delivery nanoplatforms.

Oxidative stress induced by reactive oxygen species (ROS) overproduction would hinder bone healing process at the interface of bone/implant, yet underlying mechanism remains to be explored. To endow titanium (Ti) substrates with antioxidant activity for enhanced bone formation, multilayered structure composing of chitosan-catechol (Chi-C), gelatin (Gel) and hydroxyapatite (HA) nanofibers was constructed on Ti substrates. Surface wettability and topography of multilayer coated Ti substrates were characterized by water contact angle measurement, scanning electron microscopy and atomic force microscopy, respectively. Chi-C containing multilayer on Ti surface effectively protected osteoblasts from ROS damage, which was revealed by high level of intracellular ROS scavenging activity and reduced oxidative damage on cellular level by regulating the expression of cell adhesion related genes (integrin αv, β3, CDH11 and CDH2). Moreover, it regulated the production of cell adhesive and anti-apoptotic related proteins (p-MYPT1, p-FAK, p-Akt and Bcl-2) and pro-apoptotic critical executioners (Bax and cleaved caspase 3). Beside, the composite multilayer of Chi-C/Gel/HA nanofibers on Ti substrates promoted osteoblasts differentiation, which was evidenced by high expression levels of alkaline phosphatase activity, collagen secretion, ECM mineralization and osteogenesis-related genes expression in vitro. The in vivo experiments of μ-CT analysis, push out test and histochemistry staining further confirmed that Chi-C multilayered implant had great potential for improved early bone healing. Overall, the study offers an effective strategy for the exploration of high quality Ti implants for orthopedic applications., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This study reports a reactive oxygen species (ROS) sensitive drug delivery system based on amphiphilic polymer of poly(propylene sulfide)-polyethylene glycol-serine-folic acid (PPS-mPEG-Ser-FA). The polymer could form homogeneous micelles with an average diameter of around 80 nm through self-assembly, which would then be loaded with the singlet oxygen-generating photosensitizer of zinc phthalocyanine (ZNPC) and anti-cancer drug of DOX. The disassembly of micelles could be triggered by the hydrophobic to hydrophilic transition of the PPS core in response to ROS-induced oxidation in vitro. ZNPC molecules are capable of producing ROS under laser irradiation, which results in the rapid disassembly of micelles and releasing of the anti-tumor drug for tumor therapy under physiological condition otherwise. Moreover, the excessive ROS production deriving from ZNPC synergically induces cells apoptosis. Furthermore, the DOX loaded amphiphilic micelles could be internalized by tumor cells via FA receptor-mediated endocytosis to effectively inhibit the tumor growth in vivo, while with only minimal toxic side effects. The results in vitro and in vivo consistently demonstrate that the light-responsive micelle is a promising biodegradable nanocarrier for on-command drug release and targeted tumor therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

For various chronic wounds, bacterial infection is one of the important reasons that hinder their healing. Ion‐crosslinked antibacterial hydrogel dressings based on Ag+, Cu2+ and Zn2+, have made progress in clinical application. However, the toxicity of released metal ions cannot be ignored. Therefore, how to ensure the antibacterial performance of hydrogel dressing while reducing the amount of metal ions is a major challenge for the fabrication of metal ion based antibacterial hydrogel. In this study, a general method is proposed to design cationic ion‐crosslinked hydrogel based on thiourea groups. Taking the hydrogel formed by mixing thiourea modified hyaluronic acid (H‐ANCSN) with Ag+ (HA‐NCSN/Ag+ hydrogel) as an example, the characteristics and application potential of this kind of hydrogel are thoroughly explored. Due to the strong cationic chelation characteristics of thiourea groups, HA‐NCSN/Ag+ hydrogel can gel at low Ag+ concentration and achieve long‐term slow release of Ag+ at stable concentration to balance the antibacterial and biocompatible properties. Moreover, this dynamic thiourea‐Ag+ crosslinking also endowed the hydrogel with the property of "gelation and encapsulation first, injection to cover wound when necessary". Then, the mangiferin self‐assembled nanoparticles are loaded into HA‐NCSN/Ag+ hydrogel as the radical oxygen species scavenger. [ABSTRACT FROM AUTHOR]

The drug‐resistant bacterial‐infected skin wound is still a severe healthcare problem. Uncontrolled bacterial infection, abundant reactive oxygen species (ROS) content, and prolonged inflammatory response are detrimental to wound healing. Moreover, excessive vessel growth can result in unsatisfactory scar formation. Herein, a three‐step regenerative strategy based on a bilayered gelatin/acryloyl β‐cyclodextrin (BGACD) hydrogel containing physical host–guest complexations and chemical crosslinks is proposed. The hydrogel is loaded with humic acids (HAs) and astragaloside IV (AS) in the lower layer and verteporfin (Vt) in the upper layer. Different gelatin/acryloyl β‐cyclodextrin ratios endow the lower and upper layers of the hydrogel with different degradation rates. Under light irradiation, the combination of HAs‐induced photothermal therapy (PTT) and verteporfin‐induced photodynamic therapy effectively inhibits MRSA growth. The HAs and astragaloside IV are released from the lower layer to scavenge ROS and promote M2 macrophage polarization and angiogenesis during the inflammation and early proliferation phases, while verteporfin releases from the upper layer suppress excessive vessel growth during the late proliferation and remodeling phases. The HAs‐AS@Vt@BGACD hydrogel successfully achieves rapid and scarless wound healing in an MRSA‐infected wound model in rats. Therefore, the HAs‐AS@Vt@BGACD hydrogel shows promising potential for the treatment of drug‐resistant bacteria‐infected skin wound healing. [ABSTRACT FROM AUTHOR]

The use of non‐antibiotic strategies to combat refractory drug‐resistant bacterial infections, especially biofilms and accompanying inflammation, has recently aroused widespread interest. Herein, a photo‐therapeutic nanocomposite with bio‐responsive oxygen (O2) self‐supplying is introduced by integrating manganese dioxide (MnO2) nanozymes onto photosensitizer (indocyanine green, ICG)‐loaded mesoporous polydopamine nanoparticles (MPDA), namely MI‐MPDA NPs. MI‐MPDA can activate O2 generation in the infection microenvironment, thereby effectively alleviating biofilm hypoxia. Under near‐infrared light (NIR) irradiation, continuous O2 supplying further boosts the level of singlet oxygen (1O2), enabling robust biofilm elimination through O2‐potentiated photodynamic/photothermal therapy. Interestingly, MI‐MPDA down‐regulates the factor expression of inflammatory signaling pathways through MnO2‐mediated reactive oxygen species scavenging, which ameliorates the inflammatory condition. Meanwhile, O2 supplying prevents the M1‐phenotype switch of macrophages from the overexpression of hypoxia‐inducible factor‐1α (HIF‐1α), thereby prompting macrophage reprogramming toward pro‐regenerative M2‐phenotype. In the mouse models of subcutaneous implant‐associated infection caused by methicillin‐resistant Staphylococcus aureus (MRSA) biofilms and burn infection caused by Pseudomonas aeruginosa biofilms, NIR‐irradiated MI‐MPDA not only effectively eliminates the formed biofilms, but also alleviates the oxidative stress and accompanying inflammation, and drives the cascade reaction of immunomodulation‐wound healing. Overall, this O2‐potentiated photo‐therapeutic strategy provides a reliable tool for combating biofilm infections and inflammation from drug‐resistant bacteria. [ABSTRACT FROM AUTHOR]

Despite the accuracy advantages of photothermal therapy (PTT), heat stress‐initiated free radicals and damage‐activated immune cells form a malignant positive feedback cycle following light irradiation. Herein, a 2D allomelanin nanomodulator with perpendicularly oriented oligomer planes is prepared by the guidance of DNA to achieve timely scavenging of reactive oxygen species (ROS) for inflammation and prognosis control following PTT. A large exposure degree of phenol groups and the effective transfer of delocalized electrons result in ultra‐fast redox reactions that can be boosted by a self‐amplifying process through structure disintegration. Compared with conventional photothermal agents, the nanodisks reduce the accumulation of ROS during PTT by 25‐fold, downregulate the proinflammatory factors, and adjust inflammation levels to baseline. Thereby, successful modulation of M2‐type macrophages in paratumor tissues significantly prevents burn wound progression and accelerates tissue repair, while well‐controlled neutrophil extracellular traps and largely recruited CD4+/CD8+ T cells (1.6–3.2‐fold) in the ablation site suppress the relapse of distant tumors. The study provides a useful inspiration on rationally modulating redox active nanostructures to address prognosis issues following PTT. [ABSTRACT FROM AUTHOR]

Despite the immense potential of immune checkpoint blockade (ICB) therapy in tumor treatment, its widespread clinical application is currently limited by unsatisfactory curative effect and off‐target adverse effect. Herein, an injectable sericin (SS)/silk fibroin (SF) recombinant hydrogel, termed SF‐SS‐SMC hydrogel, is developed to enable local delivery of anti‐CD47 antibody (α CD47). The hydrogel displays self‐reinforcement in high H2O2 concentration of tumor microenvironment (TME), as the SS/Fe2+ supramolecular nanocomplex (SS‐SMC) inside the hydrogel converts H2O2 to reactive oxygen species (ROS), further triggering additional crosslinking among the SF polymers. Therefore, the SF‐SS‐SMC hydrogel has an in vivo retention time longer than 21 days and acts as a reservoir for the long‐term sustained release of α CD47. More importantly, the SF‐SS‐SMC hydrogel itself efficiently regulates the remodeling of a protumor immunosuppressive TME to an antitumoral TME through switching of tumor‐associated macrophages from an anti‐inflammatory M2 phenotype to a proinflammatory M1 phenotype without additional drugs. Based on the combined effect of sustained α CD47 release and TME reprogramming, the SF‐SS‐SMC hydrogel has satisfactory immunotherapeutic effects in the treatment of local, abscopal, remitting, and metastatic tumors. Further advantages, including low cost of production, simple fabrication, and ease of use, make it promising for commercial mass production. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) driven endoplasmic reticulum (ER) stress is highly promising for tumor therapy but restrained by the nondurable introduction and limited lifetime of oxidative species. Here, a therapeutic nanosystem with sustainable ROS generation ability was developed by accommodating luminol derivatives (L012) in hyaluronic acid‐modified metal‐organic frameworks of Fe3+ and porphyrin ligand (TCPP). After particle accumulation in the tumor, ∙OH radicals from Fe3+ sites catalyzed conversion of H2O2 can react with confined L012 transducers to generate chemiluminescence (CL). Because of the distance constraints, the CL energy was significantly extracted (96%) by adjacent TCPP and further activate oxygen to long‐lifetime singlet oxygen (1O2), whose yield can be further boosted by the catalase‐like activity of the frameworks. By regulating the substrate consumption through energy conversion, the cascade process resulted in increased ROS levels (2.4‐fold) and sustainable oxidation (24 h), which induced continuously accumulated ER stress, high autophagic levels, and amplified lethality against the tumor. This work opens a new avenue to explore reticular nanostructures with complementarily arranged and synergistically spaced conversion units in advancing ROS therapy. [ABSTRACT FROM AUTHOR]

The use of reactive oxygen species (ROS) generators based on single‐atom catalysts (SACs) has been an emerging strategy for mediating tumor therapy, however, the current systems suffer from low mass transport efficiency. Here, a novel strategy of morphology fragmentation is developed to fabricate flower‐like SAC nanozymes with greatly improved 3D accessibility of active sites. Specifically, the coordinationally polymerized zeolite imidazole framework acts as a polyphenol oxidase‐like enzyme to catalyze the in situ polymerization of polydopamine (PDA) which leads to blockage of micropores and crosslinking of the morphology‐deteriorated ZIF nanosheets. The protective carbonization by PDA results in SAC nanozymes (C‐NFs) with plenty of reopened micropores and defect mesopores (≈4 nm) in the nanopetals, large interpetal pore space (≈39 nm), high surface area (388 m2 g−1), as well as an ultrahigh loading metal atoms (27.3 wt%). Subsequently, a superior peroxidases‐like activity (36.6‐fold increment in the turnover frequency) facilitates significantly strengthened ROS generation and damage of biomolecules. Moreover, the employment of apoferritin modification/loading leads to particle dispersion in solution and concomitant drug loading. The following cancer cell re‐sensitization is proven to be advantageous for boosting ROS‐facilitated treatment of drug‐resistant tumors, opening up new avenues for ROS therapy. [ABSTRACT FROM AUTHOR]

The therapeutic efficiency of reactive oxygen species (ROS)‐based nanotherapeutics is restrained by the rigorous production conditions of relatively sufficient and kinetically matching supply of intracellular substrates. The cumulative disruption of redox homeostasis and consequent pathology (e.g., Parkinson's disease) with low levels of substrates in living organisms may provide a promising model for ROS‐based therapy. Herein, a catechol chemistry‐mediated ternary nanostructure is prepared for long‐lasting generation of oxidative •OH in weakly acidic, low H2O2 homeostasis conditions of tumor. This platform employs mesoporous polydopamine (MPDA) as the porous redox mediator, while PDA‐induced sequential precipitation and biomineralization lead to hydroxy iron oxide (FeOOH) as the "iron reservoir," and calcium phosphate (CaP) as the pH‐sensitive sheddable shell. In weakly acidic conditions, the CaP layer can be degraded to expose the catalytic surface of Fe‐dopamine interplay, where FeOOH dissolution, Fe(III) chelation, Fe(III) reduction, Fe(II) release take place sequentially and continuously for Fe(II) recycling and Fenton catalysis. Both in vitro and in vivo studies verify the significant inhibition of cancer cells and tumor regression, which can also be strengthened by the local photothermal heating. This work establishes the first paradigm of pathologically inspired nanohybrids of ROS generators with long‐lasting efficacy for cancer therapy. [ABSTRACT FROM AUTHOR]

To comparatively investigate the cytotoxicities of nanomaterials in circulation, in this study, three different types of nanoparticles (NPs; mesoporous SiO2, Fe3O4, and TiO2) with diameters of around 100 nm were synthesized. The morphologies, crystalline phases, and zeta potentials of those NPs were characterized by scanning electron microscopy, X-ray diffraction and zeta potential measurement, respectively. Then, we investigated the influences of different NPs on the biological functions of endothelial cells, in particular of the organelle of cells. The results indicated that different types of NPs had cytotoxic effects in a dose- and time-dependent manner, and there was no significant difference in cytotoxicity between SiO2 and Fe3O4 at concentrations <0.20 mg/mL. The shape and surface charges of NPs greatly affected cellular internalization. We found that cytoskeleton and integrity of cells were destroyed by different NPs. Additionally, the production of reactive oxygen species damaged the mitochondria of cells, in turn leading to cells apoptosis and death. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1726-1736, 2014. [ABSTRACT FROM AUTHOR]

Innovative solutions are required for the intervention of implant associated infections (IAIs), especially for bone defect patients with chronic inflammatory diseases like diabetes mellitus (DM). The complex immune microenvironment of infections renders implants with direct antibacterial ability inadequate for the prolonged against of bacterial infections. Herein, a synergistic treatment strategy was presented that combined sonodynamic therapy (SDT) with adaptive immune modulation to treat IAIs in diabetes patients. A multifunctional coating was created on the surface of titanium (Ti) implants, consisting of manganese dioxide nanoflakes (MnO 2 NFs) with cascade catalytic enzyme activity and a responsive degradable hydrogel containing a sonosensitizer. The reactive oxygen species (ROS) generated by glucose-hydrogen peroxide (H 2 O 2) cascade catalysis and ultrasound (US) activation sonosensitizer helped kill bacteria and release bacterial antigens. Meanwhile, Mn2+ facilitated dendritic cells (DCs) maturation, enhancing antigen presentation to activate both cellular and humoral adaptive immunity against bacterial infections. This approach effectively eliminated bacteria in established diabetic IAIs model and activated systemic antibacterial immunity, providing long-term antibacterial protection. This study presents a non-antibiotic immunotherapeutic strategy for fighting IAIs in chronic diseases. [ABSTRACT FROM AUTHOR]

Titanium (Ti) and titanium alloy are the most common metal materials in clinical orthopedic surgery. However, in the initial stage of surgery and implantation, the production of excessive reactive oxygen species (ROS) can induce oxidative stress (OS) microenvironment. OS will further inhibit the growth of new bone, resulting in surgical failure. In this study, based on the fact that nanoscale manganese dioxide (MnO 2) can show H 2 O 2 -like enzyme activity, a MnO 2 nanocoating was prepared on mciro-nano structured surface of Ti substrate via a two-step method of alkaline thermal and hydrothermal treatment. The results of scanning electron microscopy (SEM), X-ray diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS) showed that the nano-MnO 2 coating was successfully fabricated on the surface of Ti substrate. The results of measurement of H 2 O 2 , dissolved O 2 and intracellular ROS in vitro showed that the treated Ti substrate could efficiently eliminate H 2 O 2 and reduce ROS. Furthermore, the modified Ti substrate could promote the early adhesion, proliferation and osteogenic differentiation of MSCs, which was demonstrated by experimental results of cell morphology, cell viability, alkaline phosphatase, collagen, and mineralization deposition. The results of quantitative real-time polymerase chain reaction (qRT-PCR) of MSCs adhered the modified Ti substrate showed that the expression of genes related to osteogenic differentiation significantly increased. More importantly, the modified Ti implant could eliminate ROS at the injury site, reduce OS and promote the regeneration of bone tissue, which was demonstrated via hematoxylin/eosin, Masson's trichrome and immunohistochemical staining. In conclusion, the modified Ti implant presented here had the effect of reducing OS and promoting osseointegration. Relevant research ideas and results provide new methods for the research and development of functional implants, which have potential application value in the field of orthopedics. • MnO 2 nanocoating was fabricated on Ti substrates via alkali thermal and hydrothermal treatment. • The modified Ti substrates effectively eliminated excess ROS and reduced OS. • The modified Ti substrates promoted adhesion, proliferation and osteogenic differentiation of MSCs. • The process of bone healing and repairing in vivo was obviously accelerated. [ABSTRACT FROM AUTHOR]

The study reports a multifunctional nanoplatform based on mesoporous silica coated gold nanorod (AuNR@MSN) to overcome biological barriers associating with nanocarrier for multiple enhanced photodynamic therapy (PDT) and photothermal therapy (PPT). Indocyanine green (ICG) was loaded into AuNR@MSN and end-capped with β-cyclodextrin (β-CD). Then, a peptide RLA ([RLARLAR] 2 ) with plasma membrane permeability and mitochondria-targeting capacity was anchored to AuNR@MSN via host-gust interaction. Subsequently, a charge-reversible polymer was introduced to endow stealth property. When the nanoplatform extravasates to tumor tissue, the weak acidity in tumor microenvironment could induce the dissociation of charge-reversible polymer and re-exposure of RLA peptide. Such a pH-mediated transition could facilitate the targeted accumulation of the nanoplatform in mitochondria. Upon singular 808 nm laser irradiation, the nanoplatform displayed enhanced PDT effect through the generation of reactive oxygen species (ROS) mediated by the local electric field of AuNR, plasmonic photothermal effect, and leakage of endogenous ROS by mitochondrion-targeted PDT. Meanwhile, local hyperthermia was generated by both ICG and AuNR for PPT. The in vitro and in vivo experiments demonstrated that the composite nanoplatform had good antitumor effect with minimal side effect. This work provides new insight into the development of new phototherapeutics for oncotherapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • The genotoxicity of TiO 2 NPs was confirmed at the single-cell level. • CINP, RPA3, and PRKACA served as biomarkers of TiO2 NPs exposure. • 5 nm and 14 nm TiO 2 NPs caused a response similar to antivirus defense. • Unique gene expression patterns were found within the same exposure of TiO2 NPs. Titanium dioxide nanoparticles (TiO 2 NPs) have attracted substantial attention in various applications, including environmental remediation and nanomedicine. A detailed understanding of the toxicity of TiO 2 NPs and the underlying mechanisms is fundamental to further development of their environmental and biomedical applications. Herein, we determined the changes in the transcriptional profile of human bone marrow stromal cells (BMSCs) after a set of different sized TiO 2 NPs exposure using single-cell RNA-seq (scRNA-seq). By taking advantage of sensitivity of scRNA-seq, we found that TiO 2 NPs exposure led to profound changes in gene expression and DNA damage signaling played a pivotal role in cellular responses to TiO 2 NPs exposure. Smaller TiO 2 NPs (5, 14 nm) led to a response similar to antivirus defense, and bigger TiO 2 NPs (54, 135, and 228 nm) induced proliferation and differentiation changes in transcriptional levels. Validation experiments on representative genes showed that some genes might be served as biomarkers of TiO 2 NPs exposure. Furthermore, in vitro and in vivo analyses showed remarkable over-production of reactive oxygen species (ROS) but did not affect osteogenic differentiation potential in BMSCs. The results unveiled landscape changes in transcriptomes in BMSCs induced by TiO 2 NPs, which provides new insights into toxicity assessments of nanomaterials. [ABSTRACT FROM AUTHOR]

• Tailored upconverting nanoparticles (UCNPs) emit both UV and vis light under NIR. • UCNPs were supramolecularly loaded with DHMA photosensitizers and camptothecin (CPT). • The UV emission could initiate the release of CPT. • The visible emission could excite the DHMA for photodynamic therapy. • The PDT activity enables the lysosomal escape of the CPT for enhanced efficacy. The strategic combination of photodynamic therapy and chemotherapy has emerged as a promising treatment option for various tumor indications, which not only expands our understanding of each individual modality but also reveals new opportunities to achieve superadditive benefit via exploring their internal synergy rather than simple mixing. In this study, dual-emissive upconverting nanoparticle (UCNP) was employed to bridge the two treatment regimens to synergistically reinforce the therapeutic efficacy. The UCNP-based drug delivery nanoplatform was first co-loaded with 1,8-dihydroxy-3-methylanthraquinone (DHMA) photosensitizers and UV-activatable camptothecin prodrug (NBCCPT) and then complexed with biofunctional β-cyclodextrin species (β-CD-PEG-LA) via highly specific host-guest interactions to cap the camptothecin prodrug conjugated on the nanoparticle surface. The supramolecularly attached β-CD-PEG-LA could not only enhance the aqueous dispersity of the nanocarriers and prevent DHMA leakage, but also imbues targeting effect against asialoglycoprotein receptor-overexpressing tumor cells. The UCNP core would convert the NIR excitation (980 nm) into localized UV (360 nm) and visible (480 nm) emissions, of which the former would cleave the nitrobenzene linker to restore the cytotoxicity of CPT while the latter could excite the photosensitizer to generate reactive oxygen species (ROS). In addition to the photodynamic damage, the light-generated ROS could also facilitate the endo/lysosomal escape of the endocytosed nanoparticles and improve the overall antitumor potency in a synergistic manner. [ABSTRACT FROM AUTHOR]