Self‐Oxygenating PROTAC Microneedle for Spatiotemporally‐Confined Protein Degradation and Enhanced Glioblastoma Therapy

Abstract Glioblastoma (GBM) is the most aggressive subtype of primary brain tumors, which marginally respond to standard chemotherapy due to the blood‐brain barrier (BBB) and the low tumor specificity of the therapeutics. Herein, a double‐layered microneedle (MN) patch is rationally engineered by integrating acid and light dual‐activatable PROteolysis TArgeting Chimera (PROTAC) nanoparticles and self‐oxygenating BSA‐MnO 2 (BM) nanoparticles for GBM treatment. The MN is administrated at the tumor site to locally deliver the PROTAC prodrug and BM nanoparticles. The PROTAC nanoparticles are rapidly released from the outer layer of the MN and specifically activated in the acidic intracellular environment of tumor cells. Subsequently, near‐infrared light activates the photosensitizer to produce singlet oxygen ( 1 O 2 ) through photodynamic therapy (PDT), thereby triggering spatiotemporally‐tunable degradation of bromodomain and extraterminal protein 4 (BRD4). The BM nanoparticles, in the inner layer of the MN, serve as an oxygen supply station, and counteracts tumor hypoxia by converting hydrogen peroxide (H 2 O 2 ) into oxygen (O 2 ), thus promoting PDT and PROTAC activation. This PROTAC prodrug‐integrated MN significantly inhibits tumor growth in both subcutaneous and orthotopic GBM tumor models. This study describes the first spatiotemporally‐tunable protein degradation strategy for highly efficient GBM therapy, potentially advancing precise therapy of other kinds of refractory brain tumors.