Extracellular proteolysis has been widely exploited to activate therapeutics in diseases such as cancer; however, activated drugs often diffuse away, limiting efficacy. To address this, we coupled protease-dependent activation with membrane tethering to retain drugs at sites of disease. We adapted our “restricted interaction peptides” (RIPs), which leverage elevated proteolytic activity to conditionally activate membrane-interacting peptides that localize cargos to nearby cell membranes. RIPs enabled delivery of diverse payloads, including cytotoxins and radioisotopes. As proof of concept, we developed FRIP, a RIP engineered for cleavage by fibroblast activation protein (FAP), a protease upregulated in solid tumors and fibrosis. Global substrate profiling identified efficient P4-P4′ sequences incorporated into FRIPs. Upon activation, FRIPs mediated membrane adhesion, internalization, and lysosomal trafficking. FRIPs armed with MMAE inhibited proliferation in a FAP-dependent manner, while optical and nuclear imaging demonstrated selective tumor targeting with minimal uptake in normal tissues. FRIPs delivering MMAE or Cu-67 produced potent antitumor activity. Together, these results establish membrane tethering as a generalizable strategy to enhance the durability and efficacy of protease-activated therapeutics.