Implantable fibrous scaffold with hierarchical microstructure for the ‘on-site’ synergistic cancer therapy

[Display omitted] •The effective modulation of microenvironment at both tissue and cellular levels.•The decomposition of tumor ECM promotes intracellular delivery of nanoparticles.•Biodegradable fibrous matrix incorporated with HAase and nanoparticles.•The implanted composite fibers exhibit remarkable tumor inhibition.•Maintaining expected biosafety for potential clinical translation. The tissue-targeting delivery and intracellular transportation of therapeutics have been highly demanded for effective cancer therapy, but remains challenging. We hereby report an implantable scaffold consisting of composite fibers with unique particle-on-fiber microstructure for localized synergistic chemo-/starvation therapy. In this system, silica nanoparticles are loaded with glucose oxidase (GOx) and protected by a polydopamine (PDA) coating. A hypoxia-activated prodrug (banoxantrone, AQ4N) is absorbed at the particle surface (MGPA). Meanwhile, biodegradable fibrous scaffold, composed of polycaprolactone (PCL) and gelatin, are incorporated with hyaluronidase (HAase), and self-assembled with MGPA nanoparticles. When the composite scaffold is implanted at the tumor site, particle liberation occurs in a pH-dependent manner. HAase released effectively decomposes extracellular matrix (ECM), and thereby promote the cellular uptake of MGPA nanoparticles. Subsequently, MGPA exhausts intracellular glucose and O2, and in turn activates AQ4N to toxic AQ4. The findings indicate that this scaffold can significantly enhance accumulation of therapeutics at tumor site for a prolonged period and resulted in promoted tumor inhibition. This study has therefore proposed an alternative design of therapeutic device, potentially combining advantages of nanoparticle-form and implantable drug delivery systems, for cancer treatment with high efficacy.