Journal Article

Synergistic chemo-immunotherapy for osteosarcoma via a pH-responsive multi-component nanoparticle system

Li, Yuanfan, Sun, Xuan, Zhang, Wenchao, Li, Dapeng, Yan, Xianwen, Cang, Jie, Wu, Feipeng

2025

Overview

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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Bone cancer / Bone tumors / Calreticulin / Cardiotoxicity / Cell death / Chemotherapy / Cytotoxicity / Dendritic cells / Doxorubicin / Drug dosages / HMGB1 protein / Immune checkpoint inhibitors / Immune response / immunogenic cell death / Immunogenicity / Immunological memory / Immunomodulation / Immunoregulation / Immunotherapy / Lipid A / Lipids / Lymphocytes T / Medical prognosis / Memory cells / Metastases / Monophosphoryl lipid A / Morphology / Nanoparticles / osteosarcoma / PD-1 protein / Pediatrics / Peptides / pH effects / pH-responsive immune-modulating nanoparticles / Pharmacology / Polyethylene glycol / Polymerization / Polymers / Reagents / Sarcoma / TLR4 and STING agonists / TLR4 protein / Toxicity / Tumor microenvironment / tumor microenvironment reprogramming