A Transformable Specific‐Responsive Peptide for One‐Step Synergistic Therapy of Bladder Cancer

Abstract Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple‐administration plan and potential side effects limit its clinical application. A transformable specific‐responsive peptide (TSRP) is utilized to one‐step achieve synergistic therapy integrating anti‐tumor, anti‐angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR‐1; ii) Transformable unit could self‐assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP‐2/9 in tumor micro‐environment; iv) Immune unit, stimulate the release of immune cells when LTX‐315 (Immune‐associated oncolytic peptide) exposed. Once its binding to FGFR‐1, the TSRP could cleaved by MMP‐2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR‐1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX‐315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8⁺ T cells infiltration. All above processes together contribute to the increasing survival rate of tumor‐bearing mice by nearly 4‐folds. This work presented a unique design for the biological application of one‐step synergistic therapy of bladder cancer.