The concept of targeted protein degradation (TPD) was proposed in 1999 [1]. Two years later, the first proteolysis-targeting chimeras (PROTAC) demonstrated selective synthetic molecule-mediated protein removal inside cells selectively [2]. Unlike occupancy-driven inhibitors, TPD eliminates “undruggable” proteins by directing the proteins of interest (POI) to cellular degradation machinery, including the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (Fig. 1A) [3], [4]. A typical TPD platform comprises a POI-binding ligand, an effector (e.g., E3 ligase) recruiter, and a chemical linker [5]. The induced proximity between POI and effector triggers efficient POI degradation [6].
PROTACs, first entered clinical trials in 2019 (ARV-110/471) [7], rely heavily on E3 ligases (e.g., cereblon (CRBN) or von Hippel-Lindau (VHL)), and enable efficient degradation of intracellular targets, particularly cytosolic proteins [8]. However, clinical translation faces following challenges: poor membrane permeability, restricted tissue distribution of E3 ligases, off-target risks, and suboptimal biodistribution limiting therapeutic efficacy [9], [10]. Notably, the hook effect is a critical challenge. PROTACs preferentially form nonproductive binary complexes (“POI-PROTAC” or “E3 ligase-PROTAC”) at excessive concentrations, disrupting ternary complex assembly and reducing degradation efficiency [11]. Molecular glues (e.g., thalidomide) with lower molecular weight also exploit the UPS by directly tethering an E3 ligase to a POI without requiring a linker [12]. However, rational design for molecular glues remains challenging, and most are discovered serendipitously [13]. Emerging modalities including autophagy-targeting chimeras (AUTACs) and lysosome-targeting chimeras (LYTACs) extend targetability to extracellular, membrane, and even cytosolic proteins through the autophagy-lysosome pathway [14], [15]. Intracellular substrates reach lysosomes and are degraded via autophagolysosome, whereas membrane and secreted proteins are endocytosed into lysosomes and degraded via endosomal and lysosomal pathways [16]. AUTACs utilize K63-linked polyubiquitination to bridge LC3-labeled autophagosomes for autophagy-lysosomal degradation [17]. Autophagy-targeting chimera (AUTOTACs) [18] and autophagosome-tethering compound (ATTECs) [19], directly engage p62 and LC3, respectively, facilitating POI sequestration into the autolysosome without ubiquitination. Additionally, chaperone-mediated autophagy targeting chimeras (CMATACs) exploit chaperone-mediated autophagy (CMA) by conjugating KFERQ-like motifs to POI-binding ligands for heat shock cognate 71 kDa protein (HSC70) and lysosome-associated membrane protein type 2A (LAMP-2A)-mediated lysosomal degradation [20]. Regarding the endosome-lysosomal pathway, LYTACs utilize cell-surface lysosome-targeting receptors (LTRs) to internalize POI complexes for lysosomal degradation [21]. Multivalent glycan ligands for LTRs present synthetic challenges and are subject to variable receptor expression across tissues and cell types [22], [23]. Autophagy-lysosome targeting degraders precisely eliminate POIs via endogenous machinery, yet encounter translational challenges such as suboptimal bioavailability, off-target distribution, and synthetic complexity [24].
Nanotechnology therefore offers robust solutions for these unmet needs. Nanoparticles (NPs), a commonly used drug delivery system, enhance drug permeability and bioavailability while minimizing off-target effects and toxicity (Fig. 1B) [25], [26]. Their passive tumor-targeting via the enhanced permeability and retention (EPR) effect, coupled with endocytic uptake via clathrin-, caveolin-, or phagocytosis-mediated routes, enables intracellular delivery and subsequent fusion with lysosomes [27], [28]. With surface modification and payload customization, NPs offer a versatile platform for next-generation TPD technology [29], [30].
Here, we introduce the emerging NP-mediated targeted protein degradation (NanoTPD) in two categories (Fig. 1C). The first is TPD-loaded NPs, and the second is termed NP-mediated targeting chimeras (NanoTACs). Since TPD-loaded NPs have been extensively reviewed [31], [32], [33], our discussion will focus on the second class, i.e., NanoTACs. NanoTAC strategies are categorized by structural and degradation mechanisms, and selected cases are reviewed by summarizing their therapeutic potential and future directions in the TPD field.