Li Dapeng, Li Yuanfan, Cang Jie, Yan Xianwen, Wu Feipeng, Sun Xuan, Zhang Wenchao
Department of Spine Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
Front Pharmacol. 2025 Apr 8;16:1584245. doi: 10.3389/fphar.2025.1584245. eCollection 2025.
Osteosarcoma (OS) is the most common primary malignant bone tumor in pediatric populations. Its treatment is complicated by chemotherapy-induced toxicity and limited induction of immunogenic cell death (ICD).
To address these challenges, we developed a pH-responsive, multi-component nanoparticle system designed to co-deliver doxorubicin (DOX), monophosphoryl lipid A (MPLA), and a PD-1/PD-L1-targeting peptide, integrated with the immune-modulating polymer PEG-PC7A. The system was optimized using both one-factor-at-a-time (OFAT) and Box-Behnken design (BBD).
The optimized nanoparticles had a hydrodynamic size of 110 nm, high encapsulation efficiency (97.15%), and pH-sensitive drug release (91% at pH 6.5). In vitro studies showed enhanced ICD markers, including calreticulin exposure and ATP/HMGB1 release, aswell as synergistic dendritic cell maturation via dual STING/TLR4 pathway activation. In an orthotopic LM8 osteosarcoma model, the nanoparticles significantly suppressed tumor growth, promoted cytotoxic T lymphocyte infiltration, reduced regulatory T cells, and established long-term immune memory.
The combination of ICD induction, innate immune activation, and checkpoint blockade reprogrammed the tumor microenvironment, amplifying anti-tumor immune responses. These results demonstrate the potential of this multifunctional nanoparticle platform as an effective immunochemotherapeutic strategy for osteosarcoma, offering enhanced therapeutic efficacy and reduced systemic toxicity.
骨肉瘤（OS）是儿童群体中最常见的原发性恶性骨肿瘤。其治疗因化疗诱导的毒性和免疫原性细胞死亡（ICD）诱导有限而变得复杂。
为应对这些挑战，我们开发了一种pH响应性多组分纳米颗粒系统，旨在共同递送阿霉素（DOX）、单磷酸脂质A（MPLA）和一种靶向PD-1/PD-L1的肽，并与免疫调节聚合物PEG-PC7A整合。该系统使用单因素法（OFAT）和Box-Behnken设计（BBD）进行了优化。
优化后的纳米颗粒的流体动力学尺寸为110nm，具有高包封率（97.15%）和pH敏感的药物释放特性（在pH 6.5时释放91%）。体外研究显示ICD标志物增强，包括钙网蛋白暴露和ATP/HMGB1释放，以及通过双STING/TLR4途径激活实现协同树突状细胞成熟。在原位LM8骨肉瘤模型中，纳米颗粒显著抑制肿瘤生长，促进细胞毒性T淋巴细胞浸润，减少调节性T细胞，并建立长期免疫记忆。
ICD诱导、先天免疫激活和检查点阻断的联合作用重新编程了肿瘤微环境，增强了抗肿瘤免疫反应。这些结果证明了这种多功能纳米颗粒平台作为骨肉瘤有效免疫化疗策略的潜力，具有增强的治疗效果和降低的全身毒性。
