Programmable PROTAC delivery for precise and spatiotemporal protein degradation

Abstract

Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) has emerged as a transformative therapeutic modality for eliminating disease-causing proteins and accessing targets previously considered “undruggable”. However, the therapeutic potency of PROTACs remains limited due to their poor cell membrane permeability and suboptimal in vivo biodistribution. As such, programmable delivery of PROTACs that offer spatial and temporal control over where and when TPD occurs is urgently needed. In this review, we summarize the most recent advances in PROTAC delivery using nanoparticles, with a focus on the chemistry and surface engineering of nanoparticles that enable spatiotemporally controlled protein degradation. We discuss lipid-based, polymeric, and inorganic nanoparticles that not only deliver PROTACs but also integrate stimuli-responsive release, immune modulation, imaging capabilities, and synergistic co-therapies. By designing nanocarriers as programmable chemical interfaces that dictate where and when protein degradation occurs, we outline how rational nanocarrier design can unlock the full therapeutic potential of PROTACs. Moreover, we provide a perspective on the integration of synthetic and self-assembly chemistry to develop programmable, multifunctional PROTAC delivery and protein degradation systems for targeted therapy.