BACKGROUND:Diabetic foot ulcers (DFU) are severe complications of diabetes, posing significant health and societal challenges. Accumulation of reactive oxygen species (ROS) and elevated glucose levels are primary factors affecting diabetic wound healing. Achieving effective treatment by reducing ROS alone is challenging, as high glucose levels continuously drive ROS production. The excellent glucose-consuming capacity of lactobacilli and the antioxidant function of hydrogen undoubtedly provide good therapeutic ideas. Herein, we combined probiotic Lactobacillus reuteri with acid-responsive hydrogen-producing nanoparticles to construct probiotic active gel LR&AB@CAH to enable a cascade of glucose consumption and hydrogen production. Lactobacillus reuteri consumed overproduced glucose and thereby released lactic acid to activate nanoparticle for hydrogen production, which could neutralize excess ROS and promote wound healing. RESULTS:In vitro experiments demonstrate that LR&AB@CAH has good biocompatibility, antioxidant capacity. LR&AB@CAH reduces excess ROS, decreases oxidative substances, and boosts antioxidant enzyme activity. In a diabetic wound mouse model, it functions as a glucose scavenger and antioxidant, reducing ROS and supporting wound healing. CONCLUSION:LR&AB@CAH offers a novel strategy for the comprehensive treatment of DFU. This study provides an artificial-natural composite hydrogel for cascade therapy on diabetic wound healing, and suggests a complete management approach for diabetic oxidative stress.

Despite the promise of activatable chemotherapy, the development of a spatiotemporally controllable strategy for prodrug activation in deep tissues remains challenging. Herein, a proof-of-concept is proposed for a gold nanocluster-based strategy that utilizes X-ray irradiation to trigger the liberation of platinum (Pt)-based prodrug conjugates, thus enabling radiotherapy-directed chemotherapy. Mechanistically, the irradiated activation of prodrugs is achieved through direct photoelectron transfer from the excited-state gold nanoclusters to the Pt(IV) center, resulting in the release of cytotoxic Pt(II) agents. Compared to the traditional combination of chemotherapy and radiotherapy, this radiotherapy-directed chemotherapy strategy offers superior antitumor efficacy and safety benefits through spatiotemporal synergy at the tumor site. Additionally, this strategy elicits robust immunogenic cell death and yields profound outcomes for combined immunotherapy of breast cancer. This versatile strategy is ushering in a new era of radiation-mediated chemistry for controlled drug delivery and the precise regulation of biological processes.

The controlled activation of metal prodrugs presents an exciting opportunity for precise and safe cancer chemotherapy. A universal strategy of radiation-triggered metal prodrug activation via nanosurface energy transfer was developed to address the limitations of insufficient and easily quenched reactive species, as reported by Fangman Chen, Wen Sun, Dan Shao et al. in their Research Article (e202317943). The proposed tool led to profound outcomes for combined cancer treatment.

The cell-specific functions of nitric oxide (NO) in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis. While most biomaterials show promise by eliciting the characteristics of NO, the insufficient storage, burst release, and pro-inflammatory side effects of NO remain as challenges. Herein, we report the development of thiol-disulfide hybrid mesoporous organosilica nanoparticles (MONs) that improve the storage and sustained release of NO, broadening the therapeutic window of NO-based therapy against colitis. The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone (Dex) in the intestinal microenvironment, specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation. Mechanistically, such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol-disulfide exchange. Specifically, the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid, even after delayed treatment. Together, our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol-disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.

Mesoporous titanium nanoparticles (MTNs) have emerged as an important porous semiconductor owning to their large surface area and unique electronic/optical properties. However, the fundamental research for rational manufacturing MTNs in a highly scalable manner remains a challenge. In this study, we report a two-step flash nanocomplexation (FNC) approach to large-scalable generate MTNs through the sequential combination of two multi-inlet vortex mixers. By optimizing the concentrated titanium precursor, polyethylene glycol (PEG)-functionalized silane amount and pH, we have been able to produce MTNs with small particle size (31.5 nm), larger surface area (416.9 m²/g) and pore volume (0.59 cm3/g). Different from the traditional MTNs bulk, FNC-produced MTNs exhibited well-controlled manner and exceptional photocatalytic and antibacterial properties. Importantly, the optimized MTNs outperformed commercial P25 not only in protecting ultraviolet A (UVA)-exposed skin, but also in treating P. aeruginosa-infected wound. We believe that the high controllability and scalability of sequential flash nanocomplexation method offers great opportunities in enhancing the performance of mesoporous titanium nanoparticles.

Metal-based drugs currently dominate the field of chemotherapeutic agents; however, achieving the controlled activation of metal prodrugs remains a substantial challenge. Here, we propose a universal strategy for the radiation-triggered activation of metal prodrugs via nanosurface energy transfer (NSET). The core–shell nanoplatform (Ru-GNC) is composed of gold nanoclusters (GNC) and ruthenium (Ru)-containing organic–inorganic hybrid coatings. Upon X-ray irradiation, chemotherapeutic Ru (II) complexes were released in a controlled manner through a unique NSET process involving the transfer of photoelectron energy from the radiation-excited Ru-GNCs to the Ru-containing hybrid layer. In contrast to the traditional radiation-triggered activation of prodrugs, such an NSET-based system ensures that the reactive species in the tumor microenvironment are present in sufficient quantity and are not easily quenched. Additionally, ultrasmall Ru-GNCs preferably target mitochondria and profoundly disrupt the respiratory chain upon irradiation, leading to radiosensitization by generating abundant reactive oxygen species. Consequently, Ru-GNC-directed radiochemotherapy induces immunogenic cell death, resulting in significant therapeutic outcomes when combined with the programmed cell death-ligand 1 (PD−L1) checkpoint blockade. This NSET strategy represents a breakthrough in designing radiation-triggered nanoplatforms for metal-prodrug-mediated cancer treatment in an efficient and controllable manner.

Carbon monoxide (CO) exhibits unique abilities in sensitizing cancer radiotherapy (RT). However, the development of a highly stable CO-delivery nanosystem with sustained CO release in tumor tissues and the prevention of CO leakage into normal tissues remains a challenge. Herein, an organic-inorganic hybrid strategy is proposed to create ultrastable CO nanoreservoirs by locking an unstable iron carbonyl (FeCO) prodrug in a stable mesoporous silica matrix. Different from traditional FeCO-loading nanoplatforms, FeCO-bridged nanoreservoirs not only tethered labile FeCO in the framework to prevent unwanted FeCO leakage, but also achieved sustained CO release in response to X-ray and endogenous H2O2. Importantly, FeCO-bridged nanoreservoirs exhibited the sequential release of CO and Fe2+, thereby performing highly efficient chemodynamic therapy. Such a powerful combination of RT, gas therapy, and chemodynamic therapy boosts robust immunogenic cell death, thus enabling the elimination of deeply metastatic colon tumors with minimal side effects. The proposed organic-inorganic hybrid strategy opens a new window for the development of stable nanoreservoirs for the on-demand delivery of unstable gases and provides a feasible approach for the sequential release of CO and metal ions from metal carbonyl complexes.

The cell membrane, as the protecting frontier of cells, is closely related to crucial biological behaviors including cell growth, death, and division. Lots of fluorescent probes have been fabricated to monitor cell membranes due to their simplicity and intuitiveness. However, the efficiency of those traditional probes has been limited by their susceptibility to photobleaching and poor water solubility. In this study, we have reported Ru(II)-coumarin complexes consisting of ruthenium, 1,10-phenanthroline, and coumarin 6 to further form self-assembled nanoprobes, for cell membrane targeting and imaging. The fluorescent property could be switchable from red to green through the dynamic disassembly of nanoprobes. Compared with commercial Dil, biocompatible nanoprobes exhibited superior stability for long-term cell imaging, along with remarkedly reduced background interference. Therefore, our self-assembled nanoprobe provides a powerful solution for investigating lipid trafficking with optical imaging.

Spinal cord injury (SCI) involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages rather than prohealing M2 macrophages, and oxidative stress. Interferon regulatory factor 5 (IRF5) is a promising therapeutic target in regulation of macrophage reprogramming from the M1 to M2 phenotype. However, knockdown of IRF5 expression mediated by small interfering RNA (siRNA) is limited by instability and poor cellular uptake. In the present study, polyethylenimine-conjugated, diselenide-bridged mesoporous silica nanoparticles are tailored to regulate macrophage polarization by controllably delivering siRNA to silence IRF5. The MSN provides reactive oxygen species (ROS)-responsive degradation and release, while polyethylenimine-function offers efficient loading of siRNA-IRF5 and enhanced endosome escape. As a consequence, the intelligent nanomaterial effectively transfects the siRNA-IRF5 with its remaining high stability and bioactivity, thereby effectively regulating the M1-to-M2 macrophage conversion in vitro and in vivo. Importantly, administration of the functional nanomaterial in crush SCI mice suppresses excessive inflammation, enhances neuroprotection, and promotes locomotor restoration. Collectively, the ROS-responsive nanomedicine provides a gene silencing strategy for regulating macrophage polarization and oxidative balance in SCI repair.

Chemotherapy causes off-target toxicity and is often ineffective against solid tumors. Targeted and on-demand release of chemotherapeutics remains a challenge. Here, cancer-cell-membrane-coated mesoporous organosilica nanoparticles (MONs) containing X-ray- and reactive oxygen species (ROS)-responsive diselenide bonds for controlled release of doxorubicin (DOX) at tumor sites are developed. DOX-loaded MONs coated with 4T1 breast cancer cell membranes (CM@MON@DOX) show greater accumulation at tumor sites and prolonged blood circulation time versus an uncoated control in mice bearing 4T1 orthotopic mammary tumors. Under low-dose X-ray radiation, the DOX-loaded MONs exhibit carrier degradation-controlled release via cleavage of diselenide bonds, resulting in DOX-mediated immunogenic cell death at the tumor site. Combination with a PD-L1 checkpoint blockade further enhances inhibition of tumor growth and metastasis with low systemic toxicity. Together, the findings show the promise of these biomimetic, radiation-responsive diselenide-bond-bridged MONs in chemo-immunotherapy.

In article number 2004385, Dan Shao, Kam W. Leong, Wen-fei Dong, and co-workers present cancer-cell-membrane-coated mesoporous organosilica nanoparticles for radiation-responsive drug delivery and cancer chemo-immunotherapy. Under low-dose X-ray radiation, such biomimetic nanotherapeutics exhibit degradation-controlled drug release and induced stronger antitumor immune responses, leading to enhanced tumor regression and metastasis inhibition with low systematic toxicity when combined with anti-PD-L1.

Although differently shaped mesoporous silica is widely studied, the formation of width-consistent mesoporous silica nanorods (MSNRs) with a precisely controlled aspect ratio (AR: length/width) is challenging and has not been reported. Herein, width-consistent (100 nm) MSNRs with ARs of 2, 3, 4, 6, 8, and 10 were obtained by increasing the concentrations while maintaining the molar ratio of cetyltrimethylammonium bromide (CTAB) and tetraethyl orthosilicate (TEOS). The results demonstrated that the as-prepared MSNR with an AR of 6 (AR6) possesses high cellular-uptake efficiency and drug-loading capacity. Thus, AR6-based cancer-cell-targeting nanosystems were designed. These nanosystems encapsulated doxorubicin (DOX) into the porous channel of AR6, adsorbed glucose oxidase (GOx), and then formed a polydopamine (PDA) layer for Siramesine (Siram, a lysosome dysfunctional drug) adsorption and folic acid modification. In this design, the PDA shell could prevent the leakage of loading components and keep the activity of GOx during delivery while achieving an on-demand drug release in the targeted location and photothermal therapy under near-infrared irradiation. The increase in temperature was highly beneficial for elevating the catalytic efficiency of GOx, accelerating the consumption of intracellular glucose, and generating a relatively high level of cytotoxic H2O2, all of which enhanced starvation and oxidative therapies. Siram was employed to inhibit lysosomal metabolism and accompany GOx to reach a dual-enhanced starvation therapy effect. In addition, DOX entered the nucleus and altered DNA for chemotherapy. The results showed that the nanosystems have superior therapeutic efficacy against cancer cells and not much toxicity to normal cells. Therefore, this study provides a novel strategy for lysosome dysfunctional synergistic chemotherapy/photothermal therapy/starvation therapy/oxidative therapy based on MSNR.

Spermatogonial stem cells (SSCs) are the cornerstone of sperm production and thus perpetual male fertility. In clinics, transplantation of patient’s own SSCs into testes is a promising technique to restore fertility when male germ cells have been depleted by gonadotoxic therapies. Auto-transplantation of genetically modified SSCs even has the potential to treat male infertility caused by genetic mutations. However, SSCs are refractory to transfection approaches. Poly(amidoamine) (PAMAM) dendrimers have the unique three-dimensional architecture, surface charge, and high density of surface groups that are suitable for ligand attachment, thereby facilitating target delivery. The goal of this study was to elucidate whether PAMAM dendrimers can efficiently deliver short interfering RNAs (siRNAs) to SSCs. We introduced cyclic arginine-glycine-aspartic acid (cRGD) peptides to the fifth generation of PAMAM dendrimers (G5) to generate PAMAM-cRGD dendrimers (G5-cRGD). The characterization of G5-cRGD was detected by Fourier transform infrared spectroscope (FTIR), transmission electron microscope (TEM), and the Cell Counting Kit-8 (CCK-8) assay. Confocal microscopy and flow cytometry were used to evaluate the delivery efficiency of siRNA by G5-cRGD to SSCs. The results showed that G5-cRGD encompassing siRNA could self-assemble into spherical structures with nanoscale size and possess high transfection efficiency, excellent endosomal escape ability, and low cytotoxicity, superior to a commercial transfection reagent Lipofectamine® 2000. Moreover, we demonstrated that G5-cRGD efficiently delivered siRNAs and triggered gene silencing. This study thus provides a promising nanovector for siRNA delivery in SSCs, facilitating the future clinical application of SSC auto-transplantation with genetically modified cells with a hope to cure male infertility that is caused by genetic disorders.

Siliceous materials based intelligent drug delivery systems (DDS) have attracted numerous attentions. Unfortunately, their intrinsic biologic inertia and non-degradability are critical issues need to be addressed because it hampers further clinical translation application. Herein, disulfide-bridged mesoporous silica nanoparticles (designed as mSiO2(s-s)) have been synthesized through nucleophilic substitution reaction, which have biodegradability in simulative tumor reducing conditions. Furthermore, folic acid (FA) decorated bull serum albumin (BSA) has been modified onto the surface of mSiO2(s-s) to improve tissue biocompatibility, prevent anticancer drugs leakage and endow effective targeting capacity. Therefore, the nanoparticles present good biodegradability, tissue biocompatibility, tumor cell targeting capacity and pH/glutathione (GSH) dual-responsive drug release capacity. This novel drug nanocarrier possesses biosafety and effective anti-cancer strategy, provides significant promising in future biomedical application.