Bone-Targeted Nanosystems Induce Multiple Types of Cell Death and Suppress Osteoclasts via Sonodynamic Sensitization Therapy to Treat Bone Metastatic Tumors.
A metal-organic framework (MOF) sonosensitizer (PN20@Rx) for treating bone metastases was designed through alendronate sodium (ALN)-mediated defect engineering, which significantly increased sonocatalytic efficiency by narrowing the interstitial spaces and optimizing the sonic-to-electrical energy conversion.
Abstract
Sonodynamic therapy (SDT) has enormous potential to eradicate tumors in situ and reshape antitumor immunity, but the efficacy of SDT is constrained by sonosensitizer performance and the intensity of the induced immune response. In the present study, a metal-organic framework (MOF) sonosensitizer (PN20@Rx) for treating bone metastases was designed through alendronate sodium (ALN)-mediated defect engineering. This strategy significantly increased sonocatalytic efficiency by narrowing the interstitial spaces and optimizing the sonic-to-electrical energy conversion. Furthermore, PN20@Rx exhibited multiple nanoenzyme activities and bone-targeting properties, simultaneously depleting glutathione (GSH), generating hydroxyl radicals (•OH), and producing oxygen (O2). In a bone metastasis model, upon ultrasound (US) stimulation, PN20@Rx effectively cleared 4T1 cells within mouse tibiae, inhibited tumor-associated bone destruction, and induced multiple regulated cell death (RCD) pathways and immunogenic cell death (ICD). PN20@Rx simultaneously downregulated the expression of the CD47 immune checkpoint protein on tumor cell surfaces, thereby converting the tumor from an immune "cold" state to an immune "hot" state and effectively suppressing lung metastasis. The present study provides a unique sonocatalytically enhanced strategy and novel insights for MOF-based clinical tumor immunotherapy.
Current clinical interventions for solid tumors are confronted with multiple prominent challenges, including intratumoral hypoxia, constitutively activated endogenous antioxidant defense systems, and inefficient tumor targeting. In this study, a multifunctional nanoliposome carrier is developed by co-encapsulation of hemoglobin (Hb), ferric citrate (FC), and chlorin e6 (Ce6), and surface-modified with the iRGD (CRGDKGPDC) peptide to facilitate active tumor targeting and enhance subsequent intratumoral penetration. Under ultrasound irradiation, the iRGD-targeted nanoliposomes can efficiently generate two distinct types of reactive oxygen species (ROS) to produce strong synergistic cytotoxicity against 4T1 breast cancer cells via separate pathways: singlet oxygen (1O₂) through the sonodynamic therapy (SDT) pathway, and hydroxyl radicals (·OH) through the chemodynamic therapy (CDT) pathway. In vivo experimental results show that tail vein injection (i.v.) of iRGD-targeted nanoliposomes combined with external ultrasound irradiation achieves can significantly enhance tumor growth inhibition, which is attributed to triggered on-demand drug release induced by ultrasound. The as-prepared iRGD-targeted nanoliposomes exhibit remarkable synergistic antitumor efficacy, inducing extensive tumor necrosis, apoptosis, and ferroptosis while causing minimal systemic side effects, demonstrating great application potential for future breast cancer therapy.
Runming Zhong, Yingzhe Wu, Yanzhen Lou et al.· Colloids and Surfaces B: Bio...· 0 citations
Cancer is one of the leading causes of death worldwide. Chemotherapy (CT) is one of the main clinical treatment modalities; however, it has limitations as a single treatment approach. To achieve a multi-modal synergistic therapy, this study designed and synthesized two amphiphilic molecules, PEG-SS-CPT and HA-SS-Ce6, and subsequently constructed intelligent nanoparticles HPCT through self-assembly, which possess both active targeting and glutathione (GSH) responsiveness for CT and sonodynamic therapy (SDT). This system employs hyaluronic acid (HA) to specifically target tumor cells that exhibit elevated CD44 expression. It responds to the high levels of GSH present in the tumor microenvironment, allowing for the release of CT drug camptothecin (CPT), while also producing singlet oxygen through Ce6 activation under ultrasound (US) stimulation, thereby simultaneously inducing apoptosis and ferroptosis in tumor cells. In the CT26 colon cancer-bearing mouse model, HPCT combined with US demonstrated a significant synergistic anti-tumor effect, with a tumor growth inhibition rate of 80.4 ± 3.1%, and did not cause significant systemic toxicity. This study indicates that through the rational design of intelligent nanoparticles integrating CT and SDT, it is possible to effectively overcome the limitations of single treatment modalities, providing a new strategy to enhance cancer treatment efficacy.
Siyu Tong, Shuang Zuo, Guodong Liu et al.· International Journal of Bio...· 0 citations
Bone metastasis is a major cause of mortality in patients with advanced breast cancer, and its treatment remains highly challenging because of the complex pathological microenvironment in bone tissue. Herein, we developed a dual-targeting nanoplatform for the cascade delivery of bisphosphonates and antitumor agents to synergistically treat breast cancer bone metastasis. Following systemic administration, zoledronic acid (ZOL)-functionalized nanoparticles Cu/ZIF@DL/SSZ-ZOL exhibit specific accumulation at bone metastasis sites, achieving drug delivery on the tissue level. Charge reversal of Cu/ZIF@DL/SSZ at the bone resorption interface leads to the detachment of ZOL and enhances the affinity of Cu/ZIF@DL/SSZ toward tumor cells, achieving drug delivery at the cellular level. After internalization by tumor cells, Cu/ZIF@DL/SSZ effectively suppress tumor cell proliferation via apoptosis, ferroptosis, and cuproptosis. The combined effects of ZOL-mediated inhibition of bone resorption and the Cu/ZIF@DL/SSZ-induced tumor inhibition effect disrupt the vicious cycle between tumor progression and bone destruction, resulting in potent antitumor efficacy. Consequently, this dual-targeting theranostic nanoagent achieves an effective treatment of breast cancer bone metastasis in animal models. Overall, this dual-targeting theranostic nanoagent offers a promising therapeutic strategy for the treatment of breast cancer bone metastases.
A dual-functional self-assembled nanoplatform integrating PDT and selective uPA inhibition for synergistic CRC treatment achieves short-term acute tumor ablation via PDT and sustained anti-metastatic potential via uPA inhibition within the tested observation windows, with favorable biosafety.
Radioimmunotherapy holds great promise for the treatment of solid tumors. However, radioresistance and immunosuppression mediated by a tumor microenvironment (TME) severely restrict radiation-induced immunogenic cell death (ICD), facilitate tumor relapse and metastatic dissemination, and ultimately compromise the therapeutic efficacy of radioimmunotherapy. Herein, we report a multifunctional cascade AuPt/SnO2–x@MOF@Arg nanoplatform to remodel TME and boost radioimmunotherapy synergistically. This system integrates X-ray-responsive peroxidase (POD), catalase(CAT), glucose oxidase (GOD), and glutathione oxidase (GSHOx) activities to achieve cascade-amplified reactive oxygen species (ROS) and controllable NO release. The structure, X-ray-induced cascade multienzyme functions, ICD activation by efficient ROS, and controllable release of high-concentration NO have been proved fully in the APSMA NPs. In vitro experiments demonstrate that a high apoptosis rate of 94.8% against 4T1 cells can be achieved by a synergistic cascade therapeutic system through inducing cell apoptosis via efficient production of ROS and arresting the cell cycle at the radiation-sensitive G2/M phase. In an in situ breast cancer model, the combined therapy effectively reduces tumor volume, and the final tumor volume is 4% of that in the X-ray group. Studies on the mechanisms underlying the immunosuppressive microenvironment reveal that NO remodels the TME by downregulating transforming growth factor beta (TGF-β), thereby inhibiting epithelial-mesenchymal transition (EMT)-associated proteins to suppress tumor metastasis and abnormal angiogenesis. Furthermore, TGF-β suppression enhances the infiltration of CD8+ T cells and reduces the proportion of FOXP3+ regulatory T cells, reversing immune suppression. This multifunctional nanozyme platform provides a robust strategy for efficient radioimmunotherapy.
Yunsong Wang, Nannan Zheng, Shujuan Liu et al.· ACS Nano· 0 citations
Rationale Since the therapeutic resistance of triple-negative breast cancer (TNBC) is mainly attributable to excessive glutathione (GSH) accumulation and its ‘cold’ immune landscape, we designed biomimetic CuZnS@BSA nanoregulators that exploit a pH-triggered ‘disarm-and-attack’ cascade, thereby initiating a well-defined, sequential therapeutic process in the acidic tumor microenvironment. Methods Biomimetic CuZnS@BSA nanoclusters were synthesized via a self-assembly method. Their pH-responsive release kinetics and synergistic therapeutic mechanisms (GSH depletion, ROS generation, and cuproptosis) were systematically evaluated in vitro using 4T1 cells. In vivo anti-tumor efficacy, immune microenvironment remodeling, and anti-metastatic effects were investigated in subcutaneous and lung metastasis TNBC mouse models, both alone and in combination with PD-L1 blockade. Results The platform first releases H2S to deplete intracellular GSH, thus removing the major antioxidant defenses of the tumor, then follows with the release of Cu2+ to induce cuproptosis, which effectively bypasses the apoptosis resistance commonly seen in TNBC. In addition, the released Zn2+ acts as an immune modulator by promoting the recognition of leaked mitochondrial DNA. This activates the cGAS-STING signaling pathway, and in vivo experiments clearly showed that it remodels the tumor microenvironment in a highly favorable manner, characterized by increased CD8+ T cell infiltration and enhanced dendritic cell maturation. Conclusion Combining this nanoregulator with PD-L1 blockade led to potent suppression of both subcutaneous tumor growth and lung metastasis, thus providing a direct, elegant link between metabolic reprogramming and systemic immune activation for TNBC therapy.
Jingyi Yang, Qi Li, Pi Zhao et al.· Theranostics· 0 citations