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Fibroblast growth factor receptor 1 (FGFR1) is emerging as a promising molecular target of lung cancer, and various FGFR1 inhibitors have exhibited significant therapeutic effects on lung cancer in preclinical research. Due to their low targeting ability or bioavailability, direct administration of these inhibitors may cause side effects. Herein, a hydrogelator, Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr-OH (Nap-Y), was rationally designed to coassemble with an FGFR1 inhibitor nintedanib (Nin) to form a peptide hydrogel Gel Y/Ninfor localized administration and FGFR1-triggered release of Nin. Upon specific phosphorylation by FGFR1 overexpressed on lung cancer cells, Nap-Yin Gel Y/Ninis converted to the hydrophilic product Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr(H2PO3)-OH (Nap-Yp), leading to dehydrogelation of the gel and subsequent Ninrelease. In vitroexperiments demonstrate that the release of Ninin a sustained manner from Gel Y/Ninsignificantly suppresses the survival, migration, and invasion of A549 cells by inhibiting FGFR1 expression and its phosphorylation function on downstream signaling molecules. Nude mouse studies show that Gel Y/Ninexhibits enhanced therapeutic efficacy on lung tumor than free Nin. We anticipate that Gel Y/Ninwill be utilized for lung cancer treatment in clinical settings in the near future.

Compared to 1H MRI, 19F MRI provides higher selectivity but lower sensitivity. Therefore, the need to inject high doses of the 19F probe to improve its sensitivity for in vivodiagnosis remains a challenge. A “smart” strategy is needed that could locally concentrate a low-dose 19F probe while avoiding the fast transverse relaxation of the probes. Locally self-assembling and disassembling 19F nanoparticles may be an optimal measure to achieve this goal. Herein, we report a dual-functional probe 1for glutathione (GSH)-controlled self-assembly and subsequent caspase 3/7 (Casp3/7)-controlled disassembly of formed nanoparticles (i.e., 1-NPs). Consecutive assembly and disassembly of 1-NPstranslate to “off” and “on” 19F magnetic resonance (MR) signal states, respectively. Employing this smart strategy, we successfully used 1for the consecutive detection of GSH and Casp3/7 activity in vitroand in cells and imaging Casp3/7 activity in cells and in zebrafish at low doses with a 14.1 T magnetic field.