Membrane Protein-Binding and Membrane-Inserting Chimeras for Cancer Therapy

High-efficiency molecular recognition tools, such as aptamers and antibodies, play a pivotal role in precise cancer theranostics. However, their noncovalent interactions with target molecules often limit their accumulation and retention within the tumor microenvironment. In this study, we introduce a class of membrane protein-targeting and membrane-inserting (MBI) chimeras, created by conjugating a membrane protein-targeting aptamer (as a model) with a pH-responsive membrane-inserting domain derived from the pH-Low Insertion Peptide (pHLIP). By harnessing the synergistic effects of these two distinct mechanisms, these MBI chimeras efficiently bind to tumor cells in the acidic microenvironment, enabling efficient delivery of chlorin e6 (Ce6) to the targeted cells. In vivo studies demonstrate that the Ce6-load MBI chimera, Sgc8-pHLIP, exhibits significantly enhanced photodynamic therapeutic efficacy compared to Ce6-loaded control constructs, which lack either membrane insertion functionality or specific membrane protein recognition. Overall, this work presents a promising strategy for the development of highly efficient molecular recognition tools for precise cancer therapeutics.