Smart multi-functional aggregates reoxygenate tumor microenvironment through a two-pronged strategy to revitalize cancer immunotherapy

PD-1/PD-L1 inhibitors have emerged as standard treatments for advanced solid tumors; however, challenges such as a low overall response rate and systemic side effects impede their implementation. Hypoxia drives the remodeling of the tumor microenvironment, which is a leading reason for the failure of immunotherapies. Despite some reported strategies to alleviate hypoxia, their individual limitations constrain further improvements. Herein, a novel two-pronged strategy is presented to efficiently address hypoxia by simultaneously adopting atovaquone (ATO, inhibiting oxygen consumption) and oxyhemoglobin (HbO2, directly supplementing oxygen) within a multifunctional aggregate termed NPs-aPD-1/HbO2/ATO. In addition to eliminating hypoxia with these two components, this smart aggregate also includes albumin and an ROS-responsive cross-linker as a controlled release scaffold, along with PD-1 antibody (aPD-1) for immunotherapy. Intriguingly, NPs-aPD-1/HbO2/ATO demonstrates exceptional tumor targeting in vivo, exhibiting approximate to 4.2 fold higher accumulation in tumors than in the liver. Consequently, this aggregate not only effectively mitigates hypoxia and significantly assists aPD-1 immunotherapy but also simultaneously resolves the targeting and systemic toxicity issues associated with individual administration of each component. This study proposes substantial implications for drug-targeted delivery, addressing tumor hypoxia and advancing immunotherapy, providing valuable insights for advancing cancer treatment strategies. Here, a smart aggregate (NPs-aPD-1/HbO2/ATO) comprised of PD-1 antibody (aPD-1), hemoglobin (Hb), atovaquone (ATO) and an ROS-responsive cross-linker is presented. Tumor ROS disrupts the linkers, releasing Hb and ATO to alleviate hypoxia via an open-source and reduce-expenditure strategy, respectively, and assisting the released aPD-1 to fight against the cancer. This approach overcomes the side effects of systemic administration of the components and profoundly advances cancer immunotherapy. image