Heterobifunctional PROteolysis TArgeting Chimeras (PROTACs) hold promising potential for cancer therapy, as they can degrade oncoproteins, particularly undruggable targets. Compared to small molecule inhibitors, PROTACs can potentially degrade any intracellular protein, including undruggable targets (e.g., transcription factors and scaffold proteins). Furthermore, PROTACs are potent agents that can circumvent acquired drug resistance by degrading whole proteins after a short drug exposure time and a low dosage. Despite being promising, conventional small molecular PROTACs generally display unfavourable pharmacokinetics and lack tumour specificity, which might cause systemic toxicity due to their nonspecific distribution in normal tissues. In this study, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment (Figure 1a). Furthermore, we engineer a dibenzocyclooctyne (DBCO)-loaded pretargeted NPs to enhance intratumoral accumulation and retention of azide-modified POLY-PROTAC NPs via in situ click reaction (Figure 1b). For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer (Figure 1c). This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.

Engineered bioorthogonal poly-protac nanoparticles for tumour-specific protein degradation and precise cancer therapy

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