Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.

Natural nanoparticles have been extensively studied due to their diverse properties and easy accessibility. Here, the nanoparticles extracted from cuttlefish ink (CINPs) with significant antitumor efficacy are explored. These CINPs, with spherical morphology, good dispersibility, and biocompatibility, are rich in melanin and contain a variety of amino acids and monosaccharides. Through the activation of mitogen-activated protein kinase (MAPK) signaling pathway, CINPs can efficiently reprogram tumor-associated macrophages (TAMs) from immune-suppressive M2-like phenotype to antitumor M1-like phenotype. Besides, under near-infrared (NIR) irradiation, CINPs exhibit high photothermal effect and tumor cell killing ability, which make them a potential candidate in photothermal therapy (PTT) of tumor. In vivo, CINPs can increase the proportion of M1 macrophages and foster the recruitment of cytotoxic T lymphocytes (CTLs) to tumors, leading to reduced primary tumor growth and lung metastasis. In combination with their photothermal effect, which can induce tumor-specific antigens release, CINPs could almost completely inhibit tumor growth accompanied by more active immune responses. Collectively, these CINPs described here can provide both tumor immunotherapy and PTT, implying that CINPs are promising for tumor treatment.

Bone and cartilage injury is common, tissue engineered scaffolds are potential means to repair. Because most of the scaffold materials used in bone and cartilage tissue engineering are bio-inert, it is necessary to increase the cellular adhesion ability of during tissue engineering reconstruction. The Arginine - Glycine - Aspartic acid (Arg-Gly-Asp, RGD) peptide family is considered as a specific recognition site for the integrin receptors. Integrin receptors are key regulators of cell-cell and cell-extracellular microenvironment communication. Therefore, the RGD polypeptide families are considered as suitable candidates for treatment of a variety of diseases and for the regeneration of various tissues and organs. Many scaffold material for tissue engineering and has been approved by US Food and Drug Administration (FDA) for human using. The application of RGD peptides in bone and cartilage tissue engineering was reported seldom. Only a few reviews have summarized the applications of RGD peptide with alloy, bone cements, and PCL in bone tissue engineering. Herein, we summarize the application progress of RGD in bone and cartilage tissue engineering, discuss the effects of structure, sequence, concentration, mechanical stimulation, physicochemical stimulation, and time stimulation of RGD peptide on cells differentiation, and introduce the mechanism of RGD peptide through integrin in the field of bone and cartilage tissue engineering.

Background/Aims: Interleukin (IL)-1β plays an essential role in the pathophysiology of osteoarthritis (OA). Cytokine response modifier A (CrmA) can prevent the generation of active IL-1β. This study aimed to explore the chondroprotective effects of hyaluronic acid-chitosan nanoparticles containing plasmid DNA encoding CrmA (HA/CS-CrmA) in a rat OA model. Methods: HA/CS-CrmA nanoparticles were synthesized through the complex coacervation of cationic polymers. The characteristics, toxicity, and transfection of the nanoparticles were investigated. Furthermore, the potential effects of HA/CS-CrmA nanoparticles were evaluated via a rat anterior cruciate ligament transection (ACLT) model of OA. Cartilage damage and synovial inflammation were assessed by safranin O/fast green and hematoxylin and eosin staining. Type II collagen in cartilage was measured by immunohistochemistry, and the expression levels of IL-1β, matrix metalloproteinase (MMP)-3, and MMP-13 in synovial tissue were detected by western blot. Results: The HA/CS-CrmA nanoparticles, which effectively entrapped plasmid DNA, showed an adequate size (100-300 nm) and a regular spherical shape. The nanoparticles safely transfected synoviocytes and released plasmid DNA in a sustained manner over 3 weeks. Additionally, HA/CS-CrmA nanoparticles significantly inhibited cartilage damage, synovial inflammation, and the loss of type II collagen induced by ACLT. The expression levels of IL-1β, MMP-3, and MMP-13 in synovial tissue were dramatically down-regulated by HA/CS-CrmA nanoparticles. Conclusions: These results suggested that HA/CS-CrmA nanoparticles could attenuate cartilage destruction and protect against early OA by inhibiting synovial inflammation via inhibition of IL-1β generation.

Over centuries, several advances have been made in osteochondral (OC) tissue engineering to regenerate more biomimetic tissue. As an essential component of tissue engineering, scaffolds provide structural and functional support for cell growth and differentiation. Numerous scaffold types, such as porous, hydrogel, fibrous, microsphere, metal, composite and decellularized matrix, have been reported and evaluated for OC tissue regeneration in vitro and in vivo, with respective advantages and disadvantages. Unfortunately, due to the inherent complexity of organizational structure and the objective limitations of manufacturing technologies and biomaterials, we have not yet achieved stable and satisfactory effects of OC defects repair. In this review, we summarize the complicated gradients of natural OC tissue and then discuss various osteochondral tissue engineering strategies, focusing on scaffold design with abundant cell resources, material types, fabrication techniques and functional properties.

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Synovial inflammation mainly resulting from interleukin-1 beta (IL-1β) plays a crucial role in the early and late stage of osteoarthritis. Recent progress in therapeutic gene delivery systems has led to promising strategies for local sustained target gene expression. The aim of this study was to design a nanoparticle made of chitosan (CS)/hyaluronic acid (HA)/plasmid-DNA (pDNA) encoding IL-1 receptor antagonist gene (pIL-1Ra) and furtherly use it to transfect the primary synoviocytes, and then investigate whether CS/HA/pIL-1Ra nanoparticles could make the synoviocytes overexpress functional IL-1Ra to attenuate inflammation induced by IL-1β. In this study, CS was modified with HA to generate CS/HA nanoparticles and then combined with pIL-1Ra to form CS/HA/pIL-1Ra nanoparticles. The physicochemical characteristics results showed that CS/HA nanoparticles exhibited an appropriate particle size (144.9 ± 2.8 nm) and positive zeta potential ( + 28 mV). The gel retardation assay revealed that pDNA was effectively protected and released in a sustained manner more than 15 days. Cytotoxicity results showed that CS/HA/pIL-1Ra nanoparticles had a safe range (0-80 μg/ml) for the application to synoviocytes. RT-qPCR and western blot analysis demonstrated that CS/HA/pIL-1Ra nanoparticles were able to increase IL-1Ra expression in primary synoviocytes, and reduce the mRNA and protein levels of matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-13 (MMP-13), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in IL-1β-induced synoviocytes. Our findings indicated that CS/HA/pIL-1Ra nanoparticles efficiently transfected synoviocytes and attenuated synovitis induced by IL-1β, which will provide a potential strategy for OA synovitis.

Traditional methods of depleting tumor-associated myeloid cells via chemotherapy can easily lead to the re-recruitment of them, eventually resulting in chemo-resistance and setting obstacles to immunotherapy. Herein, we reported a...