Thread-structural microneedles loaded with engineered exosomes for annulus fibrosus repair by regulating mitophagy recovery and extracellular matrix homeostasis.

Low back pain is among the most grave public health concerns worldwide and the major clinical manifestation of intervertebral disc degeneration (IVDD). The destruction of annulus fibrosus (AF) is the primary cause of IVDD. A sustainable and stable treatment system for IVDD is lacking because of the special organizational structure and low nutrient supply of AF. We here found that IVDD results in the impaired mitochondrial function of AF tissue, and mitochondrial autophagy (mitophagy) plays a protective role in this process. We therefore reported a thread-structural microneedle (T-MN) matching the ring structure of AF. Based on the adsorption effect of laminin, our T-MN could load with bone marrow mesenchymal stem cell-derived exosomes to envelope the regulating mitophagy microRNA (miRNA 378), named as T-MN@EXO@miR-378. In general, we offered in situ locking in the defect site of AF to prevent nucleus pulposus leakage and promoted AF repair. The design of the thread structure was aimed at bionically matching the layered AF structure, thereby providing stronger adhesion. The T-MN@EXO@miR-378 effectively attached to AF and slowly released therapeutic engineered exosomes, and prevented IVDD progression by restoring mitophagy, promoting AF cell proliferation and migration, and inhibiting the pathological remodeling of the extracellular matrix. This functional system can be used as an excellent tool for sustained drug release and has a certain prospect in substituting the conventional treatment of IVDD.

Multiple influence of immune cells in the bone metastatic cancer microenvironment on tumors.

Bone is a common organ for solid tumor metastasis. Malignant bone tumor becomes insensitive to systemic therapy after colonization, followed by poor prognosis and high relapse rate. Immune and bone cells in situ constitute a unique immune microenvironment, which plays a crucial role in the context of bone metastasis. This review firstly focuses on lymphatic cells in bone metastatic cancer, including their function in tumor dissemination, invasion, growth and possible cytotoxicity-induced eradication. Subsequently, we examine myeloid cells, namely macrophages, myeloid-derived suppressor cells, dendritic cells, and megakaryocytes, evaluating their interaction with cytotoxic T lymphocytes and contribution to bone metastasis. As important components of skeletal tissue, osteoclasts and osteoblasts derived from bone marrow stromal cells, engaging in 'vicious cycle' accelerate osteolytic bone metastasis. We also explain the concept tumor dormancy and investigate underlying role of immune microenvironment on it. Additionally, a thorough review of emerging treatments for bone metastatic malignancy in clinical research, especially immunotherapy, is presented, indicating current challenges and opportunities in research and development of bone metastasis therapies.

ZIF-8-Encapsulated Pexidartinib Delivery via Targeted Peptide-Modified M1 Macrophages Attenuates MDSC-Mediated Immunosuppression in Osteosarcoma.

Adoptive cellular therapy is a promising strategy for cancer treatment. However, the effectiveness of this therapy is limited by its intricate and immunosuppressive tumor microenvironment. In this study, a targeted therapeutic strategy for macrophage loading of drugs is presented to enhance anti-tumor efficacy of macrophages. K7M2-target peptide (KTP) is used to modify macrophages to enhance their affinity for tumors. Pexidartinib-loaded ZIF-8 nanoparticles (P@ZIF-8) are loaded into macrophages to synergistically alleviate the immunosuppressive tumor microenvironment synergistically. Thus, the M1 macrophages decorated with KTP carried P@ZIF-8 and are named P@ZIF/M1-KTP. The tumor volumes in the P@ZIF/M1-KTP group are significantly smaller than those in the other groups, indicating that P@ZIF/M1-KTP exhibited enhanced anti-tumor efficacy. Mechanistically, an increased ratio of CD4+ T cells and a decreased ratio of MDSCs in the tumor tissues after treatment with P@ZIF/M1-KTP indicated that it can alleviate the immunosuppressive tumor microenvironment. RNA-seq further confirms the enhanced immune cell function. Consequently, P@ZIF/M1-KTP has great potential as a novel adoptive cellular therapeutic strategy for tumors.

Osteocyte mitochondria inhibit tumor development via STING-dependent antitumor immunity.

Bone is one of the most common sites of tumor metastases. During the last step of bone metastasis, cancer cells colonize and disrupt the bone matrix, which is maintained mainly by osteocytes, the most abundant cells in the bone microenvironment. However, the role of osteocytes in bone metastasis is still unclear. Here, we demonstrated that osteocytes transfer mitochondria to metastatic cancer cells and trigger the cGAS/STING-mediated antitumor response. Blocking the transfer of mitochondria by specifically knocking out mitochondrial Rho GTPase 1 (Rhot1) or mitochondrial mitofusin 2 (Mfn2) in osteocytes impaired tumor immunogenicity and consequently resulted in the progression of metastatic cancer toward the bone matrix. These findings reveal the protective role of osteocytes against cancer metastasis by transferring mitochondria to cancer cells and potentially offer a valuable therapeutic strategy for preventing bone metastasis.

Cancer cells reprogram to metastatic state through the acquisition of platelet mitochondria.

Metastasis is the major cause of cancer deaths, and cancer cells evolve to adapt to various tumor microenvironments, which hinders the treatment of tumor metastasis. Platelets play critical roles in tumor development, especially during metastasis. Here, we elucidate the role of platelet mitochondria in tumor metastasis. Cancer cells are reprogrammed to a metastatic state through the acquisition of platelet mitochondria via the PINK1/Parkin-Mfn2 pathway. Furthermore, platelet mitochondria regulate the GSH/GSSG ratio and reactive oxygen species (ROS) in cancer cells to promote lung metastasis of osteosarcoma. Impairing platelet mitochondrial function has proven to be an efficient approach to impair metastasis, providing a direction for osteosarcoma therapy. Our findings demonstrate mitochondrial transfer between platelets and cancer cells and suggest a role for platelet mitochondria in tumor metastasis.

KERS-Inspired Nanostructured Mineral Coatings Boost IFN-γ mRNA Therapeutic Index for Antitumor Immunotherapy.

Tumor-associated macrophage (TAM) reprogramming is a promising therapeutic approach for cancer immunotherapy; however, its efficacy remains modest due to the low bioactivity of the recombinant cytokines used for TAM reprogramming. mRNA therapeutics are capable of generating fully functional proteins for various therapeutic purposes but accused for its poor sustainability. Inspired by kinetic energy recovery systems (KERS) in hybrid vehicles, a cytokine efficacy recovery system (CERS) is designed to substantially augment the therapeutic index of mRNA-based tumor immunotherapy via a "capture and stabilize" mechanism exerted by a nanostructured mineral coating carrying therapeutic cytokine mRNA. CERS remarkably recycles nearly 40% expressed cytokines by capturing them onto the mineral coating to extend its therapeutic timeframe, further polarizing the macrophages to strengthen their tumoricidal activity and activate adaptive immunity against tumors. Notably, interferon-γ (IFN-γ) produced by CERS exhibits ≈42-fold higher biological activity than recombinant IFN-γ, remarkably decreasing the required IFN-γ dosage for TAM reprogramming. In tumor-bearing mice, IFN-γ cmRNA@CERS effectively polarizes TAMs to inhibit osteosarcoma progression. When combined with the PD-L1 monoclonal antibody, IFN-γ cmRNA@CERS significantly boosts antitumor immune responses, and substantially prevents malignant lung metastases. Thus, CERS-mediated mRNA delivery represents a promising strategy to boost antitumor immunity for tumor treatment.

Human γδ T cells induce CD8+ T cell antitumor responses via antigen-presenting effect through HSP90-MyD88-mediated activation of JNK.

Human Vγ9Vδ2 T cells have attracted considerable attention as novel alternative antigen-presenting cells (APCs) with the potential to replace dendritic cells in antitumor immunotherapy owing to their high proliferative capacity and low cost. However, the utility of γδ T cells as APCs to induce CD8+ T cell-mediated antitumor immune response, as well as the mechanism by which they perform APC functions, remains unexplored. In this study, we found that activated Vγ9Vδ2 T cells were capable of inducing robust CD8+ T cell responses in osteosarcoma cells. Activated γδ T cells also effectively suppressed osteosarcoma growth by priming CD8+ T cells in xenograft animal models. Mechanistically, we further revealed that activated γδ T cells exhibited increased HSP90 production, which fed back to upregulate MyD88, followed by JNK activation and a subsequent improvement in CCL5 secretion, leading to enhanced CD8+ T cell cross-priming. Thus, our study suggests that Vγ9Vδ2 T cells represent a promising alternative APC for the development of γδ T cell-based tumor immunotherapy.

Enhancement of T cell infiltration via tumor-targeted Th9 cell delivery improves the efficacy of antitumor immunotherapy of solid tumors.

Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy (ACT) against solid tumors. Here, we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors. Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8+ T cells, which led to improved antitumor outcomes. Mechanistically, infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation. Overall, we presented a simple, cost-effective, and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.

Remotely Temporal Scheduled Macrophage Phenotypic Transition Enables Optimized Immunomodulatory Bone Regeneration.

Precise timing of macrophage polarization plays a pivotal role in immunomodulation of tissue regeneration, yet most studies mainly focus on M2 macrophages for their anti-inflammatory and regenerative effects while the essential proinflammatory role of the M1 phenotype on the early inflammation stage is largely underestimated. Herein, a superparamagnetic hydrogel capable of timely controlling macrophage polarization is constructed by grafting superparamagnetic nanoparticles on collagen nanofibers. The magnetic responsive hydrogel network enables efficient polarization of encapsulated macrophage to the M2 phenotype through the podosome/Rho/ROCK mechanical pathway in response to static magnetic field (MF) as needed. Taking advantage of remote accessibility of magnetic field together with the superparamagnetic hydrogels, a temporal engineered M1 to M2 transition course preserving the essential role of M1 at the early stage of tissue healing, as well as enhancing the prohealing effect of M2 at the middle/late stages is established via delayed MF switch. Such precise timing of macrophage polarization matching the regenerative process of injured tissue eventually leads to optimized immunomodulatory bone healing in vivo. Overall, this study offers a remotely time-scheduled approach for macrophage polarization, which enables precise manipulation of inflammation progression during tissue healing.

Imaging topological and correlated insulating states in twisted monolayer-bilayer graphene.

Flat bands in Van der Waals heterostructure provide an ideal platform for unveiling emergent quantum electronic phases. One celebrated example is twisted monolayer-bilayer graphene, in which the effects of electronic correlation have been observed. Here, we report the observation via scanning tunnelling microscopy and spectroscopy of correlated insulating states in twisted monolayer-bilayer graphene, leading to the formation of an electron crystal phase. At integer fillings, the strong Coulomb interaction redistributes flat-band electrons within one moiré unit cell, producing an insulating state with vanishing density of states at the Fermi level. Moreover, our approach enables the direct visualization of an ordered lattice of topological torus-shaped states, generated by the interaction between the electron crystal and the non-trivial band topology of twisted monolayer-bilayer graphene. Our results illustrate an efficient strategy for entwining topological physics with strong electron correlation in twisted van der Waals structures.

Tumor Customized 2D Supramolecular Nanodiscs for Ultralong Tumor Retention and Precise Photothermal Therapy of Highly Heterogeneous Cancers.

Target therapy for highly heterogeneous cancers represents a major clinical challenge due to the lack of recurrent therapeutic targets identified in these tumors. Herein, the authors report a tumor-customized targeting photothermal therapy (PTT) strategy for highly heterogeneous cancers, by which 2D supramolecular self-assembled nanodiscs are modified with tumor-specific binding peptides identified by phage display techniques. Taking osteosarcoma (OS) as a model heterogeneous cancer, an OS targeting peptide (OTP) is first selected after biopanning and is demonstrated to successfully bind to this heterogeneous cancer cells/tissues. Successful conjugation of OTP to heptamethine cyanine (Cy7)-based 2D nanodiscs Cy7-TCF (2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran,TCF) enables the 2D nanodiscs to specifically target the heterogeneous tumor. Notably, a single dose injection of this targeted nanodisc (T-ND) not only effectively induces enhanced photothermal tumor ablation under near-infrared light, but also exhibits sevenfold increase of tumor retention time (more than 24 days) compared to generic nanomedicine. Thus, the authors' findings suggest that the combination of phage display-based affinity peptides selection and 2D supramolecular nanodiscs leads to the development of a platform technology for highly heterogeneous cancers precise therapy, offering specific tumor targeting, ultralong tumor retention, and precise PTT.

Predictive and Prognostic Biomarkers for Lung Cancer Bone Metastasis and Their Therapeutic Value.

Lung cancer is the leading cause of cancer-related death worldwide. Bone metastasis, which usually accompanies severe skeletal-related events, is the most common site for tumor distant dissemination and detected in more than one-third of patients with advanced lung cancer. Biopsy and imaging play critical roles in the diagnosis of bone metastasis; however, these approaches are characterized by evident limitations. Recently, studies regarding potential biomarkers in the serum, urine, and tumor tissue, were performed to predict the bone metastases and prognosis in patients with lung cancer. In this review, we summarize the findings of recent clinical research studies on biomarkers detected in samples obtained from patients with lung cancer bone metastasis. These markers include the following: (1) bone resorption-associated markers, such as N-terminal telopeptide (NTx)/C-terminal telopeptide (CTx), C-terminal telopeptide of type I collagen (CTx-I), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), pyridinoline (PYD), and parathyroid hormone related peptide (PTHrP); (2) bone formation-associated markers, including total serum alkaline phosphatase (ALP)/bone specific alkaline phosphatase(BAP), osteopontin (OP), osteocalcin (OS), amino-terminal extension propeptide of type I procollagen/carboxy-terminal extension propeptide of type I procollagen (PICP/PINP); (3) signaling markers, including epidermal growth factor receptor/Kirsten rat sarcoma/anaplastic lymphoma kinase (EGFR/KRAS/ALK), receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB/osteoprotegerin (RANKL/RANK/OPG), C-X-C motif chemokine ligand 12/C-X-C motif chemokine receptor 4 (CXCL12/CXCR4), complement component 5a receptor (C5AR); and (4) other potential markers, such as calcium sensing receptor (CASR), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2), cytokeratin 19 fragment/carcinoembryonic antigen (CYFRA/CEA), tissue factor, cell-free DNA, long non-coding RNA, and microRNA. The prognostic value of these markers is also investigated. Furthermore, we listed some clinical trials targeting hotspot biomarkers in advanced lung cancer referring for their therapeutic effects.

Clinical Features and Serological Markers Risk Model Predicts Overall Survival in Patients Undergoing Breast Cancer and Bone Metastasis Surgeries.

BACKGROUND: Surgical therapy of breast cancer and bone metastasis can effectively improve the prognosis of breast cancer. However, after the first operation, the relationship between preoperative indicators and outcomes in patients who underwent metastatic bone surgery remained to be studied. Purpose 1. Recognize clinical and laboratory prognosis factors available to clinical doctors before the operation for bone metastatic breast cancer patients. 2. Develop a risk prediction model for 3-year postoperative survival in patients with breast cancer bone metastasis. METHODS: From 2014 to 2020, patients who suffered from breast cancer bone metastasis and received therapeutic procedures in our institution were included for analyses (n=145). For patients who underwent both breast cancer radical surgery and bone metastasis surgery, comprehensive datasets of the parameters of interest (clinical features, laboratory factors, and patient prognoses) were collected (n=69). We performed Multivariate Cox regression to identify factors that were associated with postoperative outcome. 3-year survival prediction model and nomograms were established by 100 bootstrapping. Its benefit was evaluated by calibration plot, C-index, and decision curve analysis. The Surveillance, Epidemiology, and End Results database was also used for external validation. RESULTS: Radiotherapy for primary cancer, pathological type of metastatic breast cancer, lymph node metastasis, elevated serum alkaline phosphatase, lactate dehydrogenase were associated with postoperative prognosis. Pathological types of metastatic breast cancer, multiple bone metastasis, organ metastases, and elevated serum lactate dehydrogenase were associated with 3-year survival. Then those significant variables and serum alkaline phosphatase counts were integrated to construct nomograms for 3-year survival. The C-statistic of the established predictive model was 0.83. The calibration plot presents a graphical representation of calibration. In the decision curve analysis, the benefits are higher than those of the extreme curve. The receiver operating characteristic of the external validation of the model was 0.82, indicating a favored fitting degree of the two models. CONCLUSION: Our study suggests that several clinical features and serological markers can predict the overall survival among the patients who are about to receive bone metastasis surgery after breast cancer surgery. The model can guide the preoperative evaluation and clinical decision-making for patients. Level of evidence Level III, prognostic study.

Study on the Electrorheological Ultra-Precision Polishing Process with an Annular Integrated Electrode.

Electrorheological (ER) polishing, as a new ultra-precision super-effect polishing method, provides little damage to the workpiece surface and is suitable for polishing all kinds of small and complex curved surface workpieces. In this paper, an ER polishing tool with an annular integrated electrode is developed. The orthogonal experiments are carried out on the six influencing factors of ER polishing which include the applied voltage, the abrasive particle size, the abrasive concentration, the polishing gap, the polishing time and the tool spindle speed. The influence order of these six factors on the ER polishing is obtained. On this basis, the effect of a single process parameter of ER polishing on surface roughness is studied experimentally.