Ranit Dutta (Thayumanavan group): Many diseases are driven by overexpression of aberrant proteins, and conventional therapies mainly use occupancy-based inhibitors to block their function. Emerging degraders like PROTACs (proteolysis targeting chimeras) and LYTACs (lysosome-targeting chimeras) have garnered attention for their wide applicability, potential to overcome drug resistance, and unique mechanisms. Unlike occupancy-based drugs that temporarily inhibit, degraders bind to target proteins and direct them to waste disposal systems such as the ubiquitin-proteasome or lysosome, resulting in complete elimination. Despite their effectiveness, off-target toxicity due to non-specific accumulation in healthy tissues is a significant challenge. To address this, we engineer PROTACs as prodrugs that activate selectively in response to tumor-specific stimuli, enhancing safety by reducing toxicity in healthy cells while maintaining potent tumor-targeted activity. This is confirmed through cell viability and protein degradation assays. Additionally, we develop antibody-polymer conjugate-based LYTACs, which we named PolyTACs (polymeric lysosome-targeting chimeras), that are designed for selective multivalent interaction with target proteins overexpressed in cancer cells, thereby degraded in lysosome without co-opting lysosome-targeting receptors. The design ensures both safety in non-cancerous tissues and adaptability for targeting diverse proteins.