Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that recruit endogenous E3-ubiquitin ligases to catalytically degrade target proteins. Peptide-based PROTACs (PepTACs) extend this strategy by harnessing peptides to selectively engage traditionally “undruggable” protein targets—including mutated or post-translationally modified isoforms that are often inaccessible to small-molecule ligands. Despite their promise, PepTACs face major translational challenges due to their poor cellular internalization and rapid proteolytic degradation. Recent work from our group demonstrated that encapsulating PepTACs in ionizable lipid nanoparticles (iLNPs) markedly enhances their intracellular delivery and degradation potency against CREPT and β-catenin, oncotargets implicated in metastatic cancers driven by aberrant Wnt signaling. Building on this success, the current study investigates whether iLNP-based delivery can be repurposed to improve the efficacy of PepTACs against Estrogen Receptor α (ERα)—a mutationally plastic nuclear transcription factor critically implicated in resistance-prone, metastatic breast cancer.We found that enhancing the anionic character of the PepTAC—via poly-glutamate tagging in the PepTAC sequence and pH-tuned iLNP formulation—significantly improves PepTAC encapsulation and its corresponding intracellular uptake. Preliminary results further revealed that systematically optimized iLNP formulations enabled previously unobserved ERα degradation by a linear, anionically tagged PepTAC with a substantially improved potency. These findings inform that continued refinement of PepTAC’s sequence-dependent physicochemical properties with the iLNP formulation parameters lead to an enhanced target knockdown efficacy of PepTACs that can be translated in vivo for appropriate disease models. The overarching goal is to establish a generalizable iLNP–PepTAC platform for efficiently targeting mutationally adaptive, treatment-refractory oncoproteins with diverse peptide-based degraders—thereby expanding the reach and precision of targeted protein degradation into intracellular proteomes previously inaccessible to small-molecule therapeutics.