State Key Laboratory of High-Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics Chinese Academy of Sciences, Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences (2021RU012), Shanghai 200050, P. R. China.
Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, P. R. China.
J Am Chem Soc. 2022 May 25;144(20):8987-8999. doi: 10.1021/jacs.2c00749. Epub 2022 May 12.
Osteoporosis is a kind of global chronic bone disease characterized by progressive loss of bone mass and bone quality reduction, leading to a largely increased risk of bone fragility. In clinics, the current treatment of osteoporosis relies on the inhibition of bone damage by osteoclasts but ignores the function of immune cells in the progress of osteoporosis, leading to much compromised therapeutic efficacy. In this work, a highly effective osteoporosis-immunotherapeutic modality is established for the treatment of osteoporosis based on acid neutralization in synergy with immune microenvironment regulation by a specially designed nanocatalytic medicine, calcein functionalized calcium-aluminum-layered double hydroxide (CALC) nanosheets. Briefly, the mildly alkaline CALC nanosheets could neutralize the acidic microenvironment of osteoporosis accompanying the acidity-responsive LDH degradation. Subsequently, calcium phosphate nanoparticles (CAPs) are generated by the reaction between the released Ca from LDH degradation and endogenous phosphates, resulting in M2 phenotype anti-inflammatory differentiation of bone macrophages through a c-Maf transcriptional factor pathway and the following activity enhancements of regulatory T cells (T) and the deactivation of T helper 17 cells (T17). Both and results show an excellent therapeutic efficacy on osteoporosis featuring a significant BV/TV (%) enhancement of femurs from 6.2 to 10.7, demonstrating high feasibility of this therapeutic concept through the combined acid neutralization and immune regulation. Such an inorganic nanomaterial-based strategy provides a novel, efficient, and biosafe therapeutic modality for intractable osteoporosis treatment, which will benefit patients suffering from osteoporosis.
骨质疏松症是一种全球性的慢性骨骼疾病，其特征是骨量逐渐丧失和骨质量下降，导致骨骼脆弱的风险大大增加。在临床上，目前治疗骨质疏松症依赖于抑制破骨细胞对骨骼的破坏，但忽略了免疫细胞在骨质疏松症进展中的作用，导致治疗效果大大降低。在这项工作中，基于一种专门设计的纳米催化药物——钙黄绿素功能化钙铝层状双氢氧化物（CALC）纳米片，通过协同中和酸性微环境和调节免疫微环境，建立了一种高效的骨质疏松症免疫治疗模式，用于治疗骨质疏松症。简而言之，温和碱性的 CALC 纳米片可以中和骨质疏松症伴随的酸性微环境，同时响应 LDH 降解。随后，释放的 Ca 与内源性磷酸盐之间发生反应，生成磷酸钙纳米颗粒（CAPs），通过 c-Maf 转录因子途径导致破骨细胞向 M2 表型抗炎分化，随后增强调节性 T 细胞（T）的活性并使辅助性 T 细胞 17 （T17）失活。和 结果均显示出对骨质疏松症的优异治疗效果，股骨的 BV/TV（%）从 6.2 显著提高到 10.7，通过联合中和酸性和免疫调节，证明了这种治疗概念的高度可行性。这种基于无机纳米材料的策略为治疗难治性骨质疏松症提供了一种新颖、高效和生物安全的治疗方式，将使骨质疏松症患者受益。
