Enhanced chemotherapy and anti-metastasis with in situ nanosphere-to-nanofiber transition

In situ morphological transformation-based drug delivery represents a cutting-edge strategy at the forefront of chemotherapy, integrating individual superiority from delivery stage-dependent, spatial-resolved morphologies. However, developing tumor-specific, in vivo morphologically transformable peptide-drug system realizing enhanced chemo-therapeutic efficacy with anti-metastasis capability is still challenging, primarily due to the shortfall in promising functional peptide candidates. By delicate control over the hydrophilic-hydrophobic balance of the peptide-drug conjugate and employing the high specificity of enzyme to transform peptide into high-ordered nanostructures on tumor site, herein, we rationally designed a novel prodrug FmocFFSGP-DOX with fibroblast activation protein-α (FAP-α, overexpressed in most epithelial tumors)-responsive nanosphere-to-nanofiber transition ability. The nanoparticle morphology formed at the first place allows for efficient tumor targeting via enhanced permeability and retention (EPR) effect along with good tumor penetration and easy cell uptake. Upon FAP-α cleavage at tumor site, DOX will be released to perform its function as a chemo-drug, while the remaining motif FmocFFSGP will be morphologically transformed to fibrous structures capable of activating the immune system and inhibiting tumor metastasis, which were systematically validated by our in vivo results. We anticipate that our strategy of FAP-α responsive nanosphere-to-nanofiber transition might be a promising alternative to promote tumor chemotherapeutic outcomes, and provide basis to the new-generation of peptide-based therapeutic agents for disease treatment in the future.