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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1584245
This article is part of the Research Topic Anti-cancer Nanomedicines: From Design to Clinical Applications View all 10 articles
Synergistic chemo-immunotherapy for osteosarcoma via a pHresponsive multi-component nanoparticle system
Provisionally accepted- 1 School of Pharmacy, Jiangsu University, Zhenjiang, China
- 2 Department of Spine Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China;, Zhenjiang, China
- 3 Department of Orthopedics, Affiliated Jintan Hospital of Jiangsu University, Jintan 213200, Jiangsu, China, Jintan, China
Osteosarcoma (OS) is the most common primary malignant bone tumor in pediatric populations, and 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. This innovative system aims to synergistically enhance anti-tumor immunity by leveraging DOX-induced ICD, MPLA-mediated TLR4 activation, and PD-1/PD-L1 blockade. Formulation optimization using both one-factor-at-a-time (OFAT) and Box-Behnken design (BBD) resulted in nanoparticles with a hydrodynamic size of 110 nm, high encapsulation efficiency (97.15%), and pH-sensitive drug release (91% at pH 6.5).In vitro studies revealed enhanced ICD markers, including calreticulin exposure and ATP/HMGB1 release, as well as synergistic dendritic cells (DCs) 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.Mechanistically, the combination of ICD induction, innate immune activation, and checkpoint blockade reprogrammed the tumor microenvironment, thereby 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.
Keywords: Osteosarcoma, pH-responsive immune-modulating nanoparticles, tumor microenvironment reprogramming, Immunogenic cell death, TLR4 and STING agonists
Received: 27 Feb 2025; Accepted: 26 Mar 2025.
Copyright: © 2025 Sun, Li, Li, Cang, Yan, Wu and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xuan Sun, School of Pharmacy, Jiangsu University, Zhenjiang, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.