The idea of focused protein degradation (TPD) was proposed in 1999 [1]. Two years later, the primary proteolysis-targeting chimeras (PROTAC) demonstrated selective artificial molecule-mediated protein removing inside cells selectively [2]. In contrast to occupancy-driven inhibitors, TPD eliminates “undruggable” proteins by directing the proteins of curiosity (POI) to mobile degradation equipment, together with the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (Fig. 1A) [3], [4]. A typical TPD platform contains a POI-binding ligand, an effector (e.g., E3 ligase) recruiter, and a chemical linker [5]. The induced proximity between POI and effector triggers environment friendly POI degradation [6].
PROTACs, first entered scientific trials in 2019 (ARV-110/471) [7], rely closely on E3 ligases (e.g., cereblon (CRBN) or von Hippel-Lindau (VHL)), and allow environment friendly degradation of intracellular targets, notably cytosolic proteins [8]. Nonetheless, scientific translation faces following challenges: poor membrane permeability, restricted tissue distribution of E3 ligases, off-target dangers, and suboptimal biodistribution limiting therapeutic efficacy [9], [10]. Notably, the hook impact is a crucial problem. PROTACs preferentially type nonproductive binary complexes (“POI-PROTAC” or “E3 ligase-PROTAC”) at extreme concentrations, disrupting ternary advanced meeting and lowering degradation effectivity [11]. Molecular glues (e.g., thalidomide) with decrease molecular weight additionally exploit the UPS by instantly tethering an E3 ligase to a POI with out requiring a linker [12]. Nonetheless, rational design for molecular glues stays difficult, and most are found serendipitously [13]. Rising modalities together with autophagy-targeting chimeras (AUTACs) and lysosome-targeting chimeras (LYTACs) prolong targetability to extracellular, membrane, and even cytosolic proteins by way of the autophagy-lysosome pathway [14], [15]. Intracellular substrates attain lysosomes and are degraded through autophagolysosome, whereas membrane and secreted proteins are endocytosed into lysosomes and degraded through endosomal and lysosomal pathways [16]. AUTACs make the most of K63-linked polyubiquitination to bridge LC3-labeled autophagosomes for autophagy-lysosomal degradation [17]. Autophagy-targeting chimera (AUTOTACs) [18] and autophagosome-tethering compound (ATTECs) [19], instantly have interaction p62 and LC3, respectively, facilitating POI sequestration into the autolysosome with out ubiquitination. Moreover, chaperone-mediated autophagy focusing on chimeras (CMATACs) exploit chaperone-mediated autophagy (CMA) by conjugating KFERQ-like motifs to POI-binding ligands for warmth shock cognate 71 kDa protein (HSC70) and lysosome-associated membrane protein kind 2A (LAMP-2A)-mediated lysosomal degradation [20]. Relating to the endosome-lysosomal pathway, LYTACs make the most of cell-surface lysosome-targeting receptors (LTRs) to internalize POI complexes for lysosomal degradation [21]. Multivalent glycan ligands for LTRs current artificial challenges and are topic to variable receptor expression throughout tissues and cell sorts [22], [23]. Autophagy-lysosome focusing on degraders exactly eradicate POIs through endogenous equipment, but encounter translational challenges akin to suboptimal bioavailability, off-target distribution, and artificial complexity [24].
Nanotechnology subsequently presents sturdy options for these unmet wants. Nanoparticles (NPs), a generally used drug supply system, improve drug permeability and bioavailability whereas minimizing off-target results and toxicity (Fig. 1B) [25], [26]. Their passive tumor-targeting through the improved permeability and retention (EPR) impact, coupled with endocytic uptake through clathrin-, caveolin-, or phagocytosis-mediated routes, allows intracellular supply and subsequent fusion with lysosomes [27], [28]. With floor modification and payload customization, NPs supply a flexible platform for next-generation TPD know-how [29], [30].
Right here, we introduce the rising NP-mediated focused protein degradation (NanoTPD) in two classes (Fig. 1C). The primary is TPD-loaded NPs, and the second is termed NP-mediated focusing on chimeras (NanoTACs). Since TPD-loaded NPs have been extensively reviewed [31], [32], [33], our dialogue will give attention to the second class, i.e., NanoTACs. NanoTAC methods are categorized by structural and degradation mechanisms, and chosen circumstances are reviewed by summarizing their therapeutic potential and future instructions within the TPD subject.
