Biofilm Homeostasis Interference Therapy via 1 O2 -Sensitized Hyperthermia and Immune Microenvironment Re-Rousing for Biofilm-Associated Infections Elimination.

The recurrence of biofilm-associated infections (BAIs) remains high after implant-associated surgery. Biofilms on the implant surface reportedly shelter bacteria from antibiotics and evade innate immune defenses. Moreover, little is currently known about eliminating residual bacteria that can induce biofilm reinfection. Herein, novel "interference-regulation strategy" based on bovine serum albumin-iridium oxide nanoparticles (BIONPs) as biofilm homeostasis interrupter and immunomodulator via singlet oxygen (1 O2 )-sensitized mild hyperthermia for combating BAIs is reported. The catalase-like BIONPs convert abundant H2 O2 inside the biofilm-microenvironment (BME) to sufficient oxygen gas (O2 ), which can efficiently enhance the generation of 1 O2 under near-infrared irradiation. The 1 O2 -induced biofilm homeostasis disturbance (e.g., sigB, groEL, agr-A, icaD, eDNA) can disrupt the sophisticated defense system of biofilm, further enhancing the sensitivity of biofilms to mild hyperthermia. Moreover, the mild hyperthermia-induced bacterial membrane disintegration results in protein leakage and 1 O2 penetration to kill bacteria inside the biofilm. Subsequently, BIONPs-induced immunosuppressive microenvironment re-rousing successfully re-polarizes macrophages to pro-inflammatory M1 phenotype in vivo to devour residual biofilm and prevent biofilm reconstruction. Collectively, this 1 O2 -sensitized mild hyperthermia can yield great refractory BAIs treatment via biofilm homeostasis interference, mild-hyperthermia, and immunotherapy, providing a novel and effective anti-biofilm strategy.

Local delivery of gaseous signaling molecules for orthopedic disease therapy.

Over the past decade, a proliferation of research has used nanoparticles to deliver gaseous signaling molecules for medical purposes. The discovery and revelation of the role of gaseous signaling molecules have been accompanied by nanoparticle therapies for their local delivery. While most of them have been applied in oncology, recent advances have demonstrated their considerable potential in diagnosing and treating orthopedic diseases. Three of the currently recognized gaseous signaling molecules, nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), are highlighted in this review along with their distinctive biological functions and roles in orthopedic diseases. Moreover, this review summarizes the progress in therapeutic development over the past ten years with a deeper discussion of unresolved issues and potential clinical applications.

Glycopeptide Nanofiber Platform for Aß-Sialic Acid Interaction Analysis and Highly Sensitive Detection of Aß.

The variation of amyloid ß peptide (Aß) concentration and Aß aggregation are closely associated with the etiology of Alzheimer's diseases (AD). The interaction of Aß with the monosialoganglioside-rich neuronal cell membrane has been suggested to influence Aß aggregation. Therefore, studies on the mechanism of Aß and sialic acids (SA) interaction would greatly contribute to better understanding the pathogenesis of AD. Herein, we report a novel approach for Aß-SA interaction analysis and highly sensitive Aß detection by mimicing the cell surface presentation of SA clusters through engineering of SA-modified peptide nanofiber (SANF). The SANF displayed well-ordered 1D nanostructure with high density of SA on surface. Using FAM-labeled Aß fragments of Aß1-16, Aß16-23, and Aß24-40, the interaction between Aß and SA was evaluated by the fluorescence titration experiments. It was found that the order of the SA-binding affinity was Aß1-16 > Aß24-40 > Aß16-23. Importantly, the presence of full-length Aß1-40 monomer triggered a significant fluorescence enhancement due to the multivalent binding of Aß1-40 to the nanofiber. This fluorescent turn-on response showed high selectivity and sensitivity for Aß1-40 detection and the method was further used for Aß aggregation process monitoring and inhibitor screening. The results suggest the proposed strategy is promising to serve as a tool for mechanism study and the early diagnosis of Alzheimer's disease.

Peptide Nanotube-Templated Biomineralization of Cu2-x S Nanoparticles for Combination Treatment of Metastatic Tumor.

1D peptide nanostructures (i.e., peptide nanotubes, PNTs) exhibit tunable chemo-physical properties and functions such as improved tissue adhesion, increased cellular uptake, and elongated blood circulation. In this study, the application of PNTs as a desirable 1D template for biomineralization of Cu2-x S nanoparticles (Cu2-x S NPs, x = 1-2) is reported. Monodisperse Cu2-x S NPs are uniformly coated on the peptide nanotubes owing to the specific high binding affinity of Cu ions to the imidazole groups exposed on the surface of nanotubes. The Cu2-x S NP-coated PNTs are further covalently grafted with an oxaliplatin prodrug (Pt-CuS-PNTs) to construct a versatile nanoplatform for combination cancer therapy. Upon 808 nm laser illumination, the nanoplatform induces significant hyperthermia effect and elicits reactive oxygen species generation through electron transfer and Fenton-like reaction. It is demonstrated that the versatile nanoplatform dramatically inhibits tumor growth and lung metastasis of melanoma in a B16-F10 melanoma tumor-bearing mouse model by combined photo- and chemotherapy. This study highlights the ability of PNTs for biomineralization of metal ions and the promising potential of such nanoplatforms for cancer treatment.

Bioinspired Multivalent Peptide Nanotubes for Sialic Acid Targeting and Imaging-Guided Treatment of Metastatic Melanoma.

Tumor metastasis is considered a major cause of cancer-related human mortalities. However, it still remains a formidable challenge in clinics. Herein, a bioinspired multivalent nanoplatform for the highly effective treatment of the metastatic melanoma is reported. The versatile nanoplatform is designed by integrating indocyanine green and a chemotherapeutic drug (7-ethyl-10-hydroxycamptothecin) into phenylboronic acid (PBA)-functionalized peptide nanotubes (termed as I/S-PPNTs). I/S-PPNTs precisely target tumor cells through multivalent interaction between PBA and overexpressed sialic acid on the tumor surface in order to achieve imaging-guided combination therapy. It is demonstrated that I/S-PPNTs are efficiently internalized by the B16-F10 melanoma cells in vitro in a PBA grafting density-dependent manner. It is further shown that I/S-PPNTs specifically accumulate and deeply penetrate into both the subcutaneous and lung metastatic B16-F10 melanoma tumors. More importantly, I/S-PPNT-mediated combination chemo- and photodynamic therapy efficiently eradicates tumor and suppresses the lung metastasis of B16-F10 melanoma in an immunocompetent C57BL/6 mouse model. The results highlight the promising potential of the multivalent peptide nanotubes for active tumor targeting and imaging-guided cancer therapy.

Overview of recent advances in liposomal nanoparticle-based cancer immunotherapy.

The clinical performance of conventional cancer therapy approaches (surgery, radiotherapy, and chemotherapy) has been challenged by tumor metastasis and recurrence that is mainly responsible for cancer-caused mortalities. The cancer immunotherapy is being emerged nowadays as a promising therapeutic modality in order to achieve a highly efficient therapeutic performance while circumventing tumor metastasis and relapse. Liposomal nanoparticles (NPs) may serve as an ideal platform for systemic delivery of the immune modulators. In this review, we summarize the cutting-edge progresses in liposomal NPs for cancer immunotherapy, with focus on dendritic cells, T cells, tumor cells, natural killer cells, and macrophages. The review highlights the major challenges and provides a perspective regarding the clinical translation of liposomal nanoparticle-based immunotherapy.

Balancing Bioresponsive Biofilm Eradication and Guided Tissue Repair via Pro-Efferocytosis and Bidirectional Pyroptosis Regulation during Implant Surgery.

There is an increasingly growing demand to balance tissue repair guidance and opportunistic infection (OI) inhibition in clinical implant surgery. Herein, we developed a nanoadjuvant for all-stage tissue repair guidance and biofilm-responsive OI eradication via in situ incorporating Cobaltiprotoporphyrin (CoPP) into Prussian blue (PB) to prepare PB-CoPP nanozymes (PCZs). Released CoPP possesses a pro-efferocytosis effect for eliminating apoptotic and progressing necrotic cells in tissue trauma, thus preventing secondary inflammation. Once OIs occur, PCZs with switchable nanocatalytic capacity can achieve bidirectional pyroptosis regulation. Once reaching the acidic biofilm microenvironment, PCZs possess peroxidase (POD)-like activity that can generate reactive oxygen species (ROS) to eradicate bacterial biofilms, especially when synergized with the photothermal effect. Furthermore, generated ROS can promote macrophage pyroptosis to secrete inflammatory cytokines and antimicrobial proteins for biofilm eradication in vivo. After eradicating the biofilm, PCZs possess catalase (CAT)-like activity in a neutral environment, which can scavenge ROS and inhibit macrophage pyroptosis, thereby improving the inflammatory microenvironment. Briefly, PCZs as nanoadjuvants feature the capability of all-stage tissue repair guidance and biofilm-responsive OI inhibition that can be routinely performed in all implant surgeries, providing a wide range of application prospects and commercial translational value.

Mussel-Derived and Bioclickable Peptide Mimic for Enhanced Interfacial Osseointegration via Synergistic Immunomodulation and Vascularized Bone Regeneration.

Inadequate osseointegration at the interface is a key factor in orthopedic implant failure. Mechanistically, traditional orthopedic implant interfaces fail to precisely match natural bone regeneration processes in vivo. In this study, a novel biomimetic coating on titanium substrates (DPA-Co/GFO) through a mussel adhesion-mediated ion coordination and molecular clicking strategy is engineered. In vivo and in vitro results confirm that the coating exhibits excellent biocompatibility and effectively promotes angiogenesis and osteogenesis. Crucially, the biomimetic coating targets the integrin α2ß1 receptor to promote M2 macrophage polarization and achieves a synergistic effect between immunomodulation and vascularized bone regeneration, thereby maximizing osseointegration at the interface. Mechanical push-out tests reveal that the pull-out strength in the DPA-Co/GFO group is markedly greater than that in the control group (79.04 ± 3.20 N vs 31.47 ± 1.87 N, P < 0.01) and even surpasses that in the sham group (79.04 ± 3.20 N vs 63.09 ± 8.52 N, P < 0.01). In summary, the novel biomimetic coating developed in this study precisely matches the natural process of bone regeneration in vivo, enhancing interface-related osseointegration and showing considerable potential for clinical translation and applications.

Honeycomb-inspired ZIF-sealed interface enhances osseointegration via anti-infection and osteoimmunomodulation.

Implant-associated infections (IAIs) pose a significant threat to orthopedic surgeries. Bacteria colonizing the surface of implants disrupt bone formation-related cells and interfere with the osteoimmune system, resulting in an impaired immune microenvironment and osteogenesis disorders. Inspired by nature, a zeolitic imidazolate framework (ZIF)-sealed smart drug delivery system on Ti substrates (ZSTG) was developed for the "natural-artificial dual-enzyme intervention (NADEI)" strategy to address these challenges. The subtle sealing design of ZIF-8 on the TiO2 nanotubes ensured glucose oxidase (GOx) activity and prevented its premature leakage. In the acidic infection microenvironment, the degradation of ZIF-8 triggered the rapid release of GOx, which converted glucose into H2O2 for disinfection. The Zn2+ released from degraded ZIF-8, as a DNase mimic, can hydrolyze extracellular DNA, which further enhances H2O2-induced disinfection and prevents biofilm formation. Importantly, Zn2+-mediated M2 macrophage polarization significantly improved the impaired osteoimmune microenvironment, accelerating bone repair. Transcriptomics revealed that ZSTG effectively suppressed the inflammatory cascade induced by lipopolysaccharide while promoting cell proliferation, homeostasis maintenance, and bone repair. In vitro and in vivo results confirmed the superior anti-infective, osteoimmunomodulatory, and osteointegrative capacities of the ZSTG-mediated NADEI strategy. Overall, this smart bionic platform has significant potential for future clinical applications to treat IAIs.

Transient hearing abnormalities precede social deficits in a mouse model of autism.

Hearing abnormalities are important symptoms of autism spectrum disorders (ASDs), a neurological and developmental disorder. However, the characteristics of hearing abnormalities associated with ASD during development have not been fully investigated. We found that in Shank3B knockout mice (a high-confidence mouse model of ASD), transient hearing abnormalities can be found in auditory brainstem response, auditory cortical activity, as well as acoustic startle response. More importantly, all hearing abnormalities at 4 weeks were most prominent and preceded the onset of social deficits at 6 weeks. These hearing abnormalities gradually recovered with age. In addition, analysis of ABR data at 4 weeks using Support Vector Machine (SVM) can faithfully predict the genotype of mice with an accuracy of 85.71%. These findings not only revealed hearing changes in Shank3B knockout autistic-like mice during development, but also suggested that hearing abnormalities could potentially be used as an early and effective indicator of ASD risk.

Biofilm Microenvironment-Responsive Self-Assembly Nanoreactors for All-Stage Biofilm Associated Infection through Bacterial Cuproptosis-like Death and Macrophage Re-Rousing.

Bacterial biofilm-associated infections (BAIs) are the leading cause of prosthetic implant failure. The dense biofilm structure prevents antibiotic penetration, while the highly acidic and H2 O2 -rich biofilm microenvironment (BME) dampens the immunological response of antimicrobial macrophages. Conventional treatments that fail to consistently suppress escaping planktonic bacteria from biofilm result in refractory recolonization, allowing BAIs to persist. Herein, a BME-responsive copper-doped polyoxometalate clusters (Cu-POM) combination with mild photothermal therapy (PTT) and macrophage immune re-rousing for BAI eradication at all stages is proposed. The self-assembly of Cu-POM in BME converts endogenous H2 O2 to toxic ·OH through chemodynamic therapy (CDT) and generates a mild PTT effect to induce bacterial metabolic exuberance, resulting in loosening the membrane structure of the bacteria, enhancing copper transporter activity and increasing intracellular Cu-POM flux. Metabolomics reveals that intracellular Cu-POM overload restricts the TCA cycle and peroxide accumulation, promoting bacterial cuproptosis-like death. CDT re-rousing macrophages scavenge planktonic bacteria escaping biofilm disintegration through enhanced chemotaxis and phagocytosis. Overall, BME-responsive Cu-POM promotes bacterial cuproptosis-like death via metabolic interference, while also re-rousing macrophage immune response for further planktonic bacteria elimination, resulting in all-stage BAI clearance and providing a new reference for future clinical application.

Strategies to prevent, curb and eliminate biofilm formation based on the characteristics of various periods in one biofilm life cycle.

Biofilms are colonies of bacteria embedded inside a complicated self-generating intercellular. The formation and scatter of a biofilm is an extremely complex and progressive process in constant cycles. Once formed, it can protect the inside bacteria to exist and reproduce under hostile conditions by establishing tolerance and resistance to antibiotics as well as immunological responses. In this article, we reviewed a series of innovative studies focused on inhibiting the development of biofilm and summarized a range of corresponding therapeutic methods for biological evolving stages of biofilm. Traditionally, there are four stages in the biofilm formation, while we systematize the therapeutic strategies into three main periods precisely:(i) period of preventing biofilm formation: interfering the colony effect, mass transport, chemical bonds and signaling pathway of plankton in the initial adhesion stage; (ii) period of curbing biofilm formation:targeting several pivotal molecules, for instance, polysaccharides, proteins, and extracellular DNA (eDNA) via polysaccharide hydrolases, proteases, and DNases respectively in the second stage before developing into irreversible biofilm; (iii) period of eliminating biofilm formation: applying novel multifunctional composite drugs or nanoparticle materials cooperated with ultrasonic (US), photodynamic, photothermal and even immune therapy, such as adaptive immune activated by stimulated dendritic cells (DCs), neutrophils and even immunological memory aroused by plasmocytes. The multitargeted or combinational therapies aim to prevent it from developing to the stage of maturation and dispersion and eliminate biofilms and planktonic bacteria simultaneously.

A temperature-regulated circuit for feeding behavior.

Both rodents and primates have evolved to orchestrate food intake to maintain thermal homeostasis in coping with ambient temperature challenges. However, the mechanisms underlying temperature-coordinated feeding behavior are rarely reported. Here we find that a non-canonical feeding center, the anteroventral and periventricular portions of medial preoptic area (apMPOA) respond to altered dietary states in mice. Two neighboring but distinct neuronal populations in apMPOA mediate feeding behavior by receiving anatomical inputs from external and dorsal subnuclei of lateral parabrachial nucleus. While both populations are glutamatergic, the arcuate nucleus-projecting neurons in apMPOA can sense low temperature and promote food intake. The other type, the paraventricular hypothalamic nucleus (PVH)-projecting neurons in apMPOA are primarily sensitive to high temperature and suppress food intake. Caspase ablation or chemogenetic inhibition of the apMPOA→PVH pathway can eliminate the temperature dependence of feeding. Further projection-specific RNA sequencing and fluorescence in situ hybridization identify that the two neuronal populations are molecularly marked by galanin receptor and apelin receptor. These findings reveal unrecognized cell populations and circuits of apMPOA that orchestrates feeding behavior against thermal challenges.

Supramolecular Prodrug Nanovectors for Active Tumor Targeting and Combination Immunotherapy of Colorectal Cancer.

Immunotherapy aiming to harness the exquisite power of the immune system has emerged as a crucial part of clinical cancer management. However, only a subset of cancer patients responds to current immunotherapy because of low immunogenicity of the tumor cells and immunosuppressive tumor microenvironment. Herein, host-guest prodrug nanovectors are reported for active tumor targeting and combating immune tolerance in tumors. The prodrug nanovectors are designed by integrating hyaluronic acid (HA) and reduction-labile heterodimer of Pheophorbide A (PPa) and NLG919 into the supramolecular nanocomplexes, where PPa and NLG919 act as a photosensitizer and potent inhibitor of indoleamine 2,3-dioxygenase 1 (IDO-1), respectively. Meanwhile, HA is employed to achieve active tumor targeting by recognizing CD44 overexpressed on the surface of tumor cell membranes. Near infrared (NIR) laser irradiation triggers the release of reactive oxygen species to provoke antitumor immunogenicity and intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Meanwhile, the immunosuppressive tumor microenvironment (ITM) is reversed by NLG919-mediated IDO-1 inhibition. Combination of photodynamic immunotherapy and IDO-1 blockade efficiently eradicates CT26 colorectal tumors in the immunocompetent mice. The host-guest nanoplatform capable of eliciting effective antitumor immunity by inactivating inhibitory immune response can be applied to other immune modulators for improved cancer immunotherapy.

[Expression of miR-155 in Acute Myeloid Leukemia and Its Clinical Significance].

OBJECTIVE: To investigate the expression of microRNA-155(miR-155) in bone marrow mononuclear cells (BMMNC) of the patients with acute myeloid leukemia(AML) and its clinical significance. METHODS: Real-time quantitative PCR (qPCR) was used to detect the expression level of miR-155 in bone marrow mononuclear cells from 80 cases of AML and 11 cases of negative control patients. RESULTS: Compared with the negative control group ,the expressions of miR-155 in initial diagnosis group and remission group both increased (P<0.01), that in the initial treatment group was significantly higher than the remission group (P<0.05). The expression level of miR-155 did not significantly correlate with the clinical features of patients. Between different cytogenetic groups in AML patients, miR-155 expression levels in the moderate prognostic group and poor prognositic group were significantly higher as compared with the favorable prognosis group P<0.05, P<0.05）, but there was no significant difference between poor and moderate progrestic groups(P>0.05). The results of tracking the situation after induction therapy of newly diagnozed AML patients showed that the remission rate of initial induction in miRNA155 high expression group and low expression group were 59.09% and 87.5% (X(2) =4.8, P<0.05), and the expression level of miR-155 in initial diagnosis of patients without complete remission after chemotherapy was significantly higher than that in patients with complete remission after chemotherapy (P= 0.042). CONCLUSION: The expression of miR-155 in AML patients is high and reduced the rate of complete remission. The high expression of miR-155 is an poor prognostic factor for patients with AML.