Intracellular Delivery of Antibody‐Based Therapeutics for Targeted Oncogenic c‐Myc Degradation in Mammalian Cells and Mice

ABSTRACT Targeting the intrinsically disordered oncoprotein c‐Myc remains challenging due to its lack of druggable pockets, hindering small‐molecule inhibitor development for decades. Antibody‐based strategies utilizing TRIM21‐mediated targeted protein degradation (TPD), such as TRIM‐Away, offer a promising alternative for endogenous c‐Myc degradation but are limited by ineffective intracellular antibody delivery and uneven endogenous TRIM21 levels in various cancer cells. To overcome these, herein we disclose an acid‐responsive nanoplatform using amorphous carbonated calcium phosphate nanoparticles (ACCP NPs) for effective intracellular co‐delivery of TRIM21 and antibodies. Under mild biomimetic conditions, TRIM21‐antibody complexes were effectively mineralized and encapsulated in the formed nanoparticles. Following endocytic uptake, these acid‐sensitive ACCP NPs disassembled in endo/lysosomes, facilitating subsequent endo/lysosomal escape and cytosolic cargo release, leading to eventual intracellular TPD. In vitro, mineralized TRIM21‐antibody complexes from ACCP NPs effectively degraded various intracellular targets, particularly c‐Myc, across diverse cell types, including those that are TRIM21‐deficient. Specifically, m‐T21‐c‐Myc Ab nanoparticle degraded c‐Myc via the ubiquitin‐proteasome system and concurrently reduced MAX levels, synergistically inhibiting c‐Myc transcriptional activity. In vivo, m‐T21‐c‐Myc Ab significantly suppressed tumor growth without major organ toxicity. This work establishes ACCP NP‐based TPD as a versatile and efficient platform for TRIM21/antibody‐mediated degradation and a promising strategy for targeting other “undruggable” proteins.