Advanced nanotechnologies for protein modulation: From Nano-PROTAC to Nano-APROM

Protein homeostasis plays a pivotal role in disease pathogenesis, making targeted protein modulation a transformative approach for therapeutic development. Current protein-targeting strategies primarily converge on two complementary approaches: selective degradation of pathogenic proteins and direct modulation of aberrant protein function. Recent advances have enabled the implementation of both strategies in nanoscale architectures, exemplified by nanoscale proteolysis-targeting chimeras (nano-PROTACs) for controlled protein degradation and nanoscale artificial protein modulators (nano-APROMs) for precise functional regulation. By integrating molecular recognition with nanoscale engineering, these systems offer enhanced delivery efficiency, spatiotemporal controllability, and expanded regulatory modalities. However, fundamental questions remain regarding their structural design principles, structure-activity relationships, and the mechanisms governing dynamic nano-bio interactions. This review highlights advances in the rational design of nano-PROTACs for improved delivery and fine-tuning of ubiquitin-proteasome degradation kinetics, and atomic-level engineering strategies for nano-APROMs that enable systematic reprogramming of aberrant protein function. First, we analyze the nanoscale architectural design principles of nano-PROTACs, focusing on stimulus-responsive allosteric architectures. Subsequently, we assess therapeutic implementation approaches employing nano-PROTACs, examining both standalone treatment modalities and synergistic combination regimens. Third, we discuss the design strategies and therapeutic applications of nano-APROMs for precise and controllable protein modulation, with a focus on atomic-scale nanomaterials-based approaches, including nanocarrier-mediated targeted delivery and atomic-level engineering for protein fine-tuning. Finally, we provide a forward-looking perspective on key challenges and untapped opportunities at the forefront of protein-targeting nanomedicine, proposing actionable directions for future research and clinical development.