Fig. 1. Schematic illustration of the bioorthogonal POLY-PROTAC NPs for tumour-specific protein degradation and precise cancer therapy.

a Cartoon illustration of the azide-functionalized bioorthogonal POLY-PROTAC NPs. POLY-PROTAC was engineered by integrating an MMP-2-liable PEG chain, an acid-activatable DPA moiety and a reduction-sensitive disulfide spacer. b Schematic illustration of the extracellular acidity-triggered click reaction between POLY-PROTAC and DBCO-loaded pretargeted NPs and sequential activation of POLY-PROTAC in response to the extracellular enzyme and intracellular acidic/reductive microenvironment. c In situ click reaction-promoted protein degradation and combinatorial cancer therapy with POLY-PROTAC NPs. The POLY-PROTAC NPs showed tumour-specific accumulation and retention via a bioorthogonal click reaction with the pretargeted NPs and cleavage of the PEG corona in the tumour mass. The POLY-PROTAC NPs were then internalised into the tumour cells for BRD4 degradation and combination therapy with PDT.