A Microneedle Delivered Nanoplatform Triggering a Therapeutic Cascade in Osteosarcoma by Amplified Photo-Activated Immunochemotherapy

Abstract

Introduction To address the challenges of recurrence, metastasis, and chemoresistance in osteosarcoma therapy, this study developed a multimodal treatment strategy integrating photo-induced chemotherapy and immunomodulation. Methods The system employs mesoporous silica nanoparticles as a carrier to co-load the photosensitizer Chlorin e6 (Ce6) and the hypoxia-activated prodrug Tirapazamine (TPZ), encapsulated within a MnO2 shell. These nanoparticles are further integrated into a dissolvable microneedle patch for localized and precise drug delivery to the tumor site. Results Under laser irradiation, Ce6-mediated photodynamic therapy (PDT) not only generates reactive oxygen species (ROS) to kill tumor cells, but also exacerbates tumor hypoxia, thereby activating the cytotoxicity of TPZ. Concurrently, manganese ion (Mn2+) released from the decomposition of the MnO2 shell serves as an immune adjuvant. In vitro experiments confirmed that this system promotes cellular uptake, ROS generation, and immunogenic cell death (ICD), while also inducing the maturation of bone marrow-derived dendritic cells (BMDC) and polarizing macrophages toward the M1 phenotype. In a subcutaneous osteosarcoma xenograft tumor mouse model, the treatment significantly inhibited tumor growth with the tumor inhibition rate reaching 83%, enhanced dendritic cell maturation, reduced regulatory T cell (Treg) infiltration, and increased the infiltration of Th1 cells and cytotoxic T lymphocytes (CTLs). Discussion This study presents a promising localized immunochemotherapy approach for the enhanced treatment of osteosarcoma.