Protein-Crowned Micelles for Targeted and Synergistic Tumor-Associated Macrophage Reprogramming to Enhance Cancer Treatment

Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancers, but achieving multitarget therapy of TAMs is still challenging. Here, we develop a protein-crowned micelle system for targeted and synergistic TAM reprogramming to enhance cancer treatment. The doxorubicin-loaded micelles with a hemoglobin crown (Hb-DOXM) can bind with endogenous plasma haptoglobin to realize specific M2-type TAM targeting. Under the tumor hypoxic and acidic environments, Hb-DOXM can responsively release O2 and DOX to reduce the recruitment of TAMs by hypoxia remission and release DOX to kill M2-type TAMs and cancer cells. To reprogram TAMs adequately, the TAM-modulating drug celecoxib is further encapsulated (Hb-DOXM@Cel) to repolarize M2-type TAMs. The targeted and synergistic TAM reprogramming by Hb-DOXM@Cel can remodel the tumor microenvironment (TME) to an immunostimulatory microenvironment and augment the antitumor effect of cytotoxic T lymphocyte, thus strongly enhancing the DOX-based chemotherapy. The protein-crowned micelle strategy presents a targeted and synergistic TAM therapy tool for enhanced cancer treatment.