Enzyme-triggered orthotopic network formation from poly(amino acid) nanoparticle to suppress tumor growth and metastases

The network structures, such as extracellular matrices (ECMs) and cytoskeleton, play crucial roles in tumor progression, and regulating these structures with exogenous biomaterials shows significant potential to inhibit tumor growth and metastases. Herein, the poly(amino acid) methoxy poly(ethylene glycol)45-block-poly(O-phospho-L-tyrosine4-co-L-alanine25) (EG45-pY4A25) was designed and used to inhibit tumor growth and metastases through in situ formation of the three-dimensional (3D) network trigged by the over-expressed alkaline phosphate (ALP) intratumorally and intracellularly. EG45-pY4A25, featuring random poly(amino acid) segment, self-assembled into nanoparticle and transformed into a 3D network induced by the increased β-sheet proportion of poly(amino acid) from 17.0% to 91.0% after dephosphorylation catalyzed by ALP after 24 h. The network structure conferred distinct properties upon EG45-pY4A25, with the storage modulus (G′) of EG45-pY4A25 varied between 1042.8 and 8913.2 Pa at concentrations from 2.0 to 7.0 mM. Additionally, the in situ self-assembled network of EG45-pY4A25 inhibited growth and metastases of mouse breast cancer cells by interfering with DNA synthesis, RNA synthesis, and protein folding, resulting in an upregulation of differentially expressed genes associated with apoptosis. Moreover, the highly ordered network with a minimum width of 200 μm effectively suppressed tumor metastases. This results demonstrated that the tailor-made poly(amino acid) holds great potential in tumor therapy by regulating the tumor microenvironments by the formed network structure.