Click-constructed modular signal aptamer chimeras enable receptor-independent degradation of membrane proteins.

Cell-membrane proteins are critical mediators of signal transduction, playing essential roles in disease occurrence and progression. The emerging LYTACs (Lysosome-targeting chimeras) technology combines drug-targeting strategies with lysosomal degradation, providing a novel approach to drug development and offering new possibilities for disease therapy. However, the clinical applicability of current LYTAC degraders is limited by the variable expression of lysosome-targeting receptors (LTRs) in tissues. To overcome this limitation, we herein hijacked a YXXØ sorting signal that derived from lysosome-associated membrane protein 2a (LAMP-2a) to develop a signal aptamer platform (SApt), which exhibits high specificity for targeting membrane proteins and inducing efficient lysosomal degradation. SApts were synthesized by conjugating the YXXØ signal peptide to the aptamer's terminus through a click reaction. Our study demonstrated that SApts efficiently degrade disease-associated membrane proteins, such as PTK7, Met, and NCL, based on the inherent signals rather than specific LTR. The potent antitumor efficacy of SApts was further confirmed in a xenograft tumor model, where in vivo degradation of PTK7 was observed. Collectively, our work provides insights into the development of a simple and universal lysosomal degradation platform with potential translational value in clinical treatment.