Biomineralization-inspired Crystallization of Manganese Oxide on Silk Fibroin Nanoparticles for in vivo MR/fluorescence Imaging-assisted Tri-modal Therapy of Cancer

Regenerated silk fibroin (SF) is a type of natural biomacromolecules with outstanding biocompatibility and biodegradability. However, stimulus-responsive SF-based nanocomplex has seldom been reported for application in tumor diagnosis and therapy. Methods: As a proof-of-concept study, a multifunctional SF@MnO(2) nanoparticle-based platform was strategically synthesized using SF as a reductant and a template via a biomineralization-inspired crystallization process in an extremely facile way. Because of their mesoporous structure and abundant amino and carboxyl terminal residues, SF@MnO(2) nanoparticles were co-loaded with a photodynamic agent indocyanine green (ICG) and a chemotherapeutic drug doxorubicin (DOX) to form a SF@MnO(2)/ICG/DOX (SMID) nanocomplex. Results: The obtained product was highly reactive with endogenous hydrogen peroxide (H(2)O(2)) in tumor microenvironment, which was decomposed into O(2) to enhance tumor-specific photodynamic therapy (PDT). Moreover, SMID nanocomplex produced a strong and stable photothermal effect upon near-infrared (NIR) irradiation for photothermal therapy (PTT) owing to the distinct photothermal response of SF@MnO(2) and stably conjugated ICG. The concurrent NIR fluorescence and magnetic resonance (MR) imaging in vivo both indicated effective tumor-specific enrichment of SMID nanoparticles via enhanced permeability and retention (EPR) effect. Animal studies further verified that SMID nanoparticles remarkably improved tumor inhibitive efficacy through combination PTT/PDT/chemotherapy with minimal systemic toxicity or adverse effect. Conclusion: This study demonstrated the promising potential of SF-based nanomaterial to address some of the key challenges in cancer therapy due to unfavorable tumor microenvironment for drug delivery.