Enzyme-functionalized β-cyclodextrin silicasomes for sequential stroma remodeling and combination chemotherapy in neuroblastoma

Neuroblastoma is a high-risk cancer that develops in the nervous system of children under the age of five. One of its main challenges is that it develops a very dense desmoplastic stroma that physically obstructs the penetration of treatments and promotes the malignant capabilities of cancer cells, which rapidly develop resistance to chemotherapeutic agents. This renders traditional treatments ineffective, as the high doses required to overcome these barriers lead to severe off-target toxicities, causing irreversible damage to the patient's developing tissues. To breach this protective microenvironment, we engineered an intelligent, multi-stage nanoplatform consisting of collagenase-functionalized β-cyclodextrin silicasomes for sequential stroma remodelling and combination chemotherapy. Using extracellular matrix-biomimetic 3D neuroblastoma models, we confirmed that the surface-bound enzymatic action of the nanosystems actively degraded the components of the external stroma, facilitating deep penetration of the silicasomes into the shielded tumor core. Once inside, the nanocarriers selectively targeted cancer cells and their complementation with the β-cyclodextrin modules drove the co-delivery of complementary chemotherapeutics doxorubicin and paclitaxel, which exhibit high cytotoxicity against solid malignancies but are traditionally limited by issues related to differing pharmacokinetics. Ultimately, these findings provide an in vitro proof-of-concept for addressing stromal barriers in neuroblastoma, offering a strategy that warrants further biocompatibility and in vivo studies to validate its translational potential across stroma-rich solid tumors.