Nanotechnology enabled proximity-induced protein degradation from multiscale bottlenecks to precision therapeutics

Proximity-induced protein degradation (PIPD) extends pharmacological intervention beyond occupancy-based inhibition by exploiting endogenous proteasomal or lysosomal pathways to eliminate disease-relevant proteins. However, when targeted degradation is combined with nanotechnology-based delivery, in vivo outcomes often diverge from expectations based on in vitro activity or tissue accumulation, frequently manifesting as transient degradation and rapid protein recovery. Here, PIPD is considered an analytical framework for interpreting these in vivo behaviors rather than a discrete technological category. Durable degradation depends on the formation and persistence of effective proximity between target proteins and degradation machinery within biologically relevant compartments. Evidence across systems indicates that outcomes are constrained by interrelated factors spanning molecular requirements for productive complex formation, intracellular trafficking, and organism-level distribution and protein resynthesis. Nano-bio interfacial properties further influence ligand accessibility and intracellular routing, shaping the contexts in which proximity-driven degradation occurs. By synthesizing these multiscale constraints, this review provides a mechanism-based perspective on variability in nano-enabled PIPD systems and outlines evaluation strategies that integrate localization, degradation kinetics, and protein recovery to better guide delivery design and interpretation of in vivo efficacy.