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This study focuses on the inherent difficulties in the basic research of osteosarcoma, and constructs a bone-targeted and glutathione-responsive polymer nanoparticle system to achieve the simultaneous loading of manganese chelation and components of the two pathways. By modifying with alendronate, the carrier is endowed with the ability to selectively accumulate in bone tumors. The controlled release of active components is accomplished by leveraging the unique microenvironment characteristics of tumor cells. Through targeted intervention to regulate DNA damage-related processes, combined with manganese ions to enhance the signal transduction of the innate immune pathway, the immune-suppressive microenvironment of osteosarcoma lesions is reconstituted. The in vivo investigations confirm that this bone-specific nanosystem can intervene in the development of tumor lesions and activate the systemic immune response of the body. This review addresses the regeneration and repair challenges caused by the heterogeneity of bone-cartilage tissue, with the tissue engineering system combining mesenchymal stem cells and biomaterial scaffolds as the core. It clarifies the regulatory mechanism of biological physical signals on the fate of stem cells, systematically summarizes the progress in the design of biomimetic microenvironment scaffolds under mechanical biology guidance, and achieves precise regulation of the lineage-specific differentiation of mesenchymal stem cells, providing theoretical support and design references for layered bone-cartilage regeneration, especially the regeneration of subchondral bone. 01 Research Background
Osteosarcoma is a malignant bone tumor of high concern in clinical basic research. At present, there are two core bottlenecks in related research: Firstly, conventional functional carriers and active substances are difficult to achieve effective delivery and accumulation in bone tissue, and there is a significant deficiency in the targeting enrichment performance of bone lesions; Secondly, bone tumors are chronically in an immunosuppressive state, and the activation efficiency of the innate immune pathway is insufficient. A single pathway regulatory mode is unable to change the characteristics of the lesion microenvironment, and the existing research framework cannot meet the in-depth exploration requirements of immune regulation in bone tumors. The tendon-bone transitional tissue has a highly specialized extracellular matrix structure, with the core feature being the hierarchical arrangement of collagen and the gradient composition of minerals. This structural system can achieve stable force transmission and guide the cell phenotype of spatial organization. Currently, it is impossible to precisely reproduce the complex multi-scale structure and composition gradient at the tendon-bone interface, which has become a key bottleneck hindering the integration and regeneration of soft and hard tissues. It is urgently necessary to develop a biomimetic matrix construction scheme that conforms to the natural structure characteristics. 02 Main Content
The study focuses on the core exploration of bone-targeted delivery and the synergistic regulation of the immune pathways of bone tumors, preparing polymer nanoparticles with manganese chelation ability, and simultaneously carrying ATM and PRMT5-related inhibitory components. Using alendronate for carrier targeting optimization, it is adapted to the enrichment characteristics of bone tissue. By constructing an endogenous response drug release mechanism based on intracellular glutathione, the active components are precisely targeted to tumor cells. Through dual-targeted intervention to amplify DNA damage effects, combined with manganese ions to enhance the recognition ability of cytoplasmic DNA, the cGAS-STING innate immune pathway is continuously activated from multiple dimensions to adjust the immune microenvironment structure of bone tumors.
03 Research Design
The overall experimental design adopts a bone-targeted modification, microenvironment response, and multi-pathway synergy approach. First, a basic framework of polymer nanoparticles is established, and manganese chelation sites are constructed and active components are loaded; then, through coupling modification, bone-targeting functional groups are introduced to enhance the affinity and aggregation ability of the carrier to bone tumor tissues; using the difference in intracellular glutathione concentration as a triggering condition, a programmed release path is designed; simultaneously, the multi-level bone tumor immune activation model is built and in vivo biological effects verification exploration is carried out at the molecular level.
04 Results
The modified nanoparticles can stably achieve preferential accumulation in the tumor lesion area and precisely respond to the microenvironment of tumor cells to complete the release of active substances; dual-targeted pathway intervention can effectively enhance the DNA damage effect and initiate the activation process of the basic immune pathway; The introduction of manganese elements can further enhance the efficacy of innate immune signal transduction and reverse the local immunosuppressive state of bone tumors. At the level of in vivo experiments, this nanosystem can intervene in the pathological process of osteosarcoma and simultaneously facilitate the activation of systemic immune-related responses.
05 Extension of Ideas
This research delves deeply into the core direction of basic scientific research on bone tumors, integrating research ideas such as metal ion immune regulation, development of bone-targeted nanomaterials, and multi-pathway collaborative intervention. The logic of bone-targeted modification of carriers and endogenous response design can be extended to the development of multifunctional nanocarriers for other bone-related diseases; the regulatory mechanism of manganese ions in conjunction with the innate immune pathway can improve the basic theoretical system of immune regulation in bone tissues and also provide mature experimental ideas and theoretical support for subsequent basic explorations of multi-targeted combined regulation in the field of bone tumors.
Original Source:
1. Journal: Bioactive Materials
2. Publication Date: April 3, 2026
3. DOI: 10.1016/j.bioactmat.2026.03.032
4. Research Authors: Zhaochen Tong, Yuezhan Li, Lingpu Zhang, Sijie Wen, and other multiple researchers jointly completed
