Proteome editing offers a powerful approach for targeted protein modulation that enables post-translational degradation, stabilization, activation, or relocalization of proteins of interest (POIs) within cells. One promising proteome editing modality is ubiquibodies (uAbs), which are chimeric proteins composed of a POI-binding domain fused to an E3 ubiquitin ligase or E3 adaptor, redirecting the otherwise stable POI to the proteasome for degradation. Traditional uAb technology has relied heavily on pre-existing binding domains with affinity and specificity for a limited number of targets. To overcome this limitation, we leveraged a protein language model (pLM)-driven algorithm, SaLT&PepPr, to computationally design “guide” peptides with affinity for β-catenin, a validated cancer target that has remained beyond the reach of conventional therapeutic approaches. These peptides were fused to the catalytic domain of the human E3 ligase CHIP, creating peptide-guided uAbs. When expressed in colorectal cancer cells, these uAbs selectively degraded cytosolic and nuclear β-catenin, the pathogenic subpopulation associated with driving oncogene expression, while preserving the normal membrane-associated subpopulation, which is protective and maintains tissue integrity. Selective knockdown of pathogenic β-catenin disrupted Wnt/β-catenin signaling and impaired tumor cell proliferation. Additionally, we demonstrated the degradation of β-catenin in BALB/c mice using an optimized uAb that was delivered intravenously as LNP-encapsulated mRNA. Collectively, our results highlight the potential of uAbs to selectively target and degrade pathogenic proteins, paving the way for the development of peptide-programmable biologic modulators for other disease-associated proteins.