Bioinspired adhesive nanofibrous hydrogel promotes immune infiltration through effective immunochemotherapy for osteosarcoma treatment

Abstract

Osteosarcoma, the predominant primary malignant bone tumor, presents ongoing clinical challenges, notably in local recurrence and metastasis. Here, we introduce a nanofibrous hydrogel composed of two layers, a bottom layer consisting of catechol-functionalized gelatin hydrogel and a top layer made up of hyaluronic acid (HA) / polycaprolactone (PCL) electrospun nanofiber matrix, for dealing with bone malignancy. This nanofibrous hydrogel incorporates doxorubicin (DOX), a primary chemotherapeutic agent, followed by the release of immune-related cytokines, thereby initiating an immunotherapeutic response to target residual malignancy. Our results demonstrate that this hydrogel can conformally adhere to bone tumor sites, enabling localized treatment and reducing systemic toxicity. The anti-cancer efficacy is notably augmented through DOX-mediated cytotoxicity and the induction of immunogenic cell death, which stimulates immune cell recruitment to the tumor milieu. Exploiting the distinct degradation kinetics of HA and PCL nanofibers, we achieve a controlled and sequential liberation of IFN-γ and IL-12, thereby amplifying the immunological anti-cancer effects. In vivo assessments reveal that our nanofibrous hydrogel significantly enhances T-cell activation, facilitates lymphocyte infiltration into tumor tissue, and effectively suppresses tumor growth. This nanofibrous hydrogel demonstrates substantial potential as a drug delivery system in osteosarcoma treatment, offering a synergistic approach to immunochemotherapy applicable to various cancer types.