We　have　synthesized　a　PEGylated,　phenylboronic　acid　modified　L-DOPA　pro-antioxidant　(pPAD)　that　can　self-assemble　into　nanoparticles　(pPADN)　for　the　loading　of　a　model　glucocorticoid　dexamethasone　(Dex)　through　1,3-diol/phenylboronic　acid　chemistry　and　hydrophobic　interactions　for　more　effective　treatment　of　inflammation.　Upon　exposure　to　ROS,　pPADN　convert　into　the　active　form　of　L-DOPA,　and　a　cascade　of　oxidative　reactions　transform　it　into　antioxidative　melanin-like　materials.　Concomitantly,　the　structural　transformation　of　pPADN　triggers　the　specific　release　of　Dex,　along　with　the　acidic　pH　of　inflammatory　tissue.　In　a　rat　model　of　osteoarthritis,　Dex-loaded　pPADN　markedly　mitigate　synovial　inflammation,　suppress　joint　destruction　and　cartilage　matrix　degradation,　with　negligible　in　vivo　toxicity.　Moreover,　in　situ　structural　transformation　makes　pPADN　suitable　for　noninvasive　monitoring　of　therapeutic　effects　as　a　photoacoustic　imaging　contrast　agent.　©　2021　Wiley-VCH　GmbH