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Abstract Protein degradation techniques, such as proteolysis‐targeting chimeras (PROTACs) and lysosome‐targeting chimeras (LYTACs), have emerged as promising therapeutic strategies for the treatment of diseases. However, the efficacy of current protein degradation methods still needs to be improved to address the complex mechanisms underlying diseases. Herein, a LYTAC Plus hydrogel engineered is proposed by nucleic acid self‐assembly, which integrates a gene silencing motif into a LYTAC construct to enhance its therapeutic potential. As a proof‐of‐concept study, vascular endothelial growth factor receptor (VEGFR)‐binding peptides and mannose‐6 phosphate (M6P) moieties into a self‐assembled nucleic acid hydrogel are introduced, enabling its LYTAC capability. Small interference RNAs (siRNAs) is then employed that target the angiopoietin‐2 (ANG‐2) gene as cross‐linkers for hydrogel formation, giving the final LYTAC Plus hydrogel gene silencing ability. With dual functionalities, the LYTAC Plus hydrogel demonstrated effectiveness in simultaneously reducing the levels of VEGFR‐2 and ANG‐2 both in vitro and in vivo, as well as in improving therapeutic outcomes in treating neovascular age‐related macular degeneration in a mouse model. As a general material platform, the LYTAC Plus hydrogel may possess great potential for the treatment of various diseases and warrant further investigation.