Rapid Selenoprotein Activation by Selenium Nanoparticles to Suppresses Osteoclastogenesis and Pathological Bone Loss.

Osteoclast hyperactivation stands as a significant pathological factor contributing to the emergence of bone disorders driven by heightened oxidative stress levels. The modulation of the redox balance to scavenge reactive oxygen species emerges as a viable approach to addressing this concern. Selenoproteins, characterized by selenocysteine (SeCys2) as the active center, are crucial for selenium-based antioxidative stress therapy for inflammatory diseases. This study reveals that surface-active elemental selenium (Se) nanoparticles, particularly lentinan-Se (LNT-Se), exhibit enhanced cellular accumulation and accelerated metabolism to SeCys2, the primary active Se form in biological systems. Consequently, LNT-Se demonstrates significant inhibition of osteoclastogenesis. Furthermore, in vivo studies underscore the superior therapeutic efficacy of LNT-Se over SeCys2, potentially attributable to the enhanced stability and safety profile of LNT-Se. Specifically, LNT-Se effectively modulates the expression of the selenoprotein GPx1, thereby exerting regulatory control over osteoclastogenesis inhibition, and the prevention of osteolysis. In summary, these results suggest that the prompt activation of selenoproteins by Se nanoparticles serves to suppress osteoclastogenesis and pathological bone loss by upregulating GPx1. Moreover, the utilization of bioactive Se species presents a promising avenue for effectively managing bone disorders.

Universal Fe/Mn Nanoadjuvant with T1/T2 MRI Self-Navigation and Gas Generation for Ideal Vaccines with Precise Tracking.

Because of the distinguished properties between nanovaccine and traditional vaccine, the precise guidelines for nanovaccines with an optimal vaccination strategy to induce ideal immunities are greatly desired for combating major diseases, including cancer and infections. Herein, we designed and synthesized a self-navigating nanoadjuvant composed of Fe-doped manganese carbonate and its nanovaccine via a facile method. First, the degradation of the nanoadjuvant under acidic milieu of immune cells in lymph nodes would generate T1 and T2 MR imaging (MRI) signals to reflect the transformation dynamics of the nanovaccine and inform us when the next vaccination needed. Under this guideline, nanovaccines with a precise vaccination strategy triggered robust antigen-specific immune responses and immunological memory to effectively prevent ovalbumin (OVA)-expressing melanoma relapse by activating dendritic cells via a stimulator of interferon genes (STING) signaling pathway and inducing antigen cross-presentation by shaping lysosome integrity with CO2 generation and upregulating transporter associated antigen processing 1 (TAP-1) transporter. This study provides a universal nanoadjuvant with imaging self-guidance, immunopotentiating, and cross-priming activities for developing precise vaccines with an optimal immunization strategy to combat major diseases.

Tellurium-driven maple leaf-shaped manganese nanotherapeutics reshape tumor microenvironment via chemical transition in situ to achieve highly efficient radioimmunotherapy of triple negative breast cancer.

The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer (TNBC) is largely limited by the complicated tumor microenvironment (TME) and its immunosuppressive state. Thus developing a strategy to reshape TME is expected to achieve highly efficient radioimmunotherapy. Therefore, we designed and synthesized a tellurium (Te)-driven maple leaf manganese carbonate nanotherapeutics (MnCO3@Te) by gas diffusion method, but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer radioimmunotherapy. As expected, with the help of H2O2 in TEM, MnCO3@Te heterostructure with reversible Mn3+/Mn2+ transition could catalyze the intracellular ROS overproduction to amplify radiotherapy. In addition, by virtue of the ability to scavenge H+ in TME by carbonate group, MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes (STING) pathway activation, resulting in remodeling immuno-microenvironment. As a result, MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in vivo. Collectively, these findings indicate that MnCO3@Te as an agonist, successfully overcome radioresistance and awaken immune systems, showing promising potential for solid tumor radioimmunotherapy.

Precise Engineering of a Se/Te Nanochaperone for Reinvigorating Cancer Radio-Immunotherapy.

Facilely synthesized nanoradiosensitizers with well-controlled structure and multifunctionality are greatly desired to address the challenges of cancer radiotherapy. In this work, a universal method is developed for synthesizing chalcogen-based TeSe nano-heterojunctions (NHJs) with rod-, spindle-, or dumbbell-like morphologies by engineering the surfactant and added selenite. Interestingly, dumbbell-shaped TeSe NHJs (TeSe NDs) as chaperone exhibit better radio-sensitizing activities than the other two nanostructural shapes. Meanwhile, TeSe NDs can serve as cytotoxic chemodrugs that degrade to highly toxic metabolites in acidic environment and deplete GSH within tumor to facilitate radiotherapy. More importantly, the combination of TeSe NDs with radiotherapy significantly decreases regulatory T cells and M2-phenotype tumor-associated macrophage infiltrations within tumors to reshape the immunosuppressive microenvironment and induce robust T lymphocytes-mediated antitumor immunity, resulting in great abscopal effects on combating distant tumor progression. This study provides a universal method for preparing NHJ with well-controlled structure and developing nanoradiosensitizers to overcome the clinical challenges of cancer radiotherapy.

Selenadiazole derivative-loaded metal azolate frameworks facilitate NK cell immunotherapy by sensitizing tumor cells and shaping immuno-suppressive microenvironments.

The low sensitivity of tumor cells and immunosuppressive microenvironments lead to unsatisfactory efficacy of natural killer (NK) cell immunotherapy. In this work, we developed a safe and effective combination treatment strategy by integrating a selenadiazole derivative (PSeD)-loaded metal azolate framework (PSeD@MAF-4(R)) with NK cells derived from cancer patients against a xenograft human breast tumor model. Intriguingly, it was found that only PSeD@MAF-4(R) pretreatment on tumor cells exhibited synergistic effects with NK cells in inhibiting tumor cell growth by up-regulating NKG2D and its ligands to maximize the interactions between NK and MCF-7 cells. Moreover, PSeD@MAF-4(R) pretreatment could significantly enhance the degranulation of NK cells and regulate their secretions of pro- or anti-inflammatory cytokines (e.g. IL-6, IL-10, and TGF-ß). Furthermore, PSeD@MAF-4(R) could significantly enhance the penetration capability of NK cells into tumor spheroids. The combination treatment mainly induced G1 phase arrest and activated multiple caspase-mediated apoptosis of tumor cells. In vivo evidence showed that PSeD@MAF-4(R) combined with NK cells could highly efficiently combat breast tumor progression via inducing and activating innate immune cell (DC and NK cell) infiltrations within tumor tissues while shaping the suppressive tumor microenvironment by down-regulating the expression of TGF-ß. This developed strategy may provide important information for developing NK cell-based combination cancer immunotherapy with high efficacy and good safety profiles.

Shape-Controllable Tellurium-Driven Heterostructures with Activated Robust Immunomodulatory Potential for Highly Efficient Radiophotothermal Therapy of Colon Cancer.

Tellurium (Te)-based semiconductor easily leads to the recombination of photogenerated electron-hole pairs (h+-e-) that severely limits the efficiency of reactive oxygen species (ROS) generation and further hinders its clinical application in biomedicine. With regard to these problems, herein we designed and synthesized a Te heterostructure (BTe-Pd-Au) by incorporating palladium (Pd) and gold (Au) elements to promote its radiosensitivity and photothermal performance, thus realizing highly efficient radiophotothermal tumor elimination by activating robust immunomodulatory potential. This shape-controllable heterostructure that coated by Pd on the surface of Te nanorods and Au in the center of Te nanorods was simply synthesized by using in situ synthesis method, which could promote the generation and separation of h+-e- pairs, thereby exhibiting superior ROS producing ability and photothermal conversion efficiency. Using a mouse model of colon cancer, we proved that BTe-Pd-Au-R-combined radiophotothermal therapy not only eradicated tumor but also elicited to a series of antitumor immune responses by enhancing the cytotoxic T lymphocytes, triggering dendritic cells maturation, and decreasing the percentage of M2 tumor-associated macrophages. In summary, our study highlights a facile strategy to design Te-driven heterostructure with versatile performance in radiosensitization, photothermal therapy, and immunomodulation and offers great promise for clinical translational treatment of colon cancer.