An on‐Demand Oxygen Nano‐vehicle Sensitizing Protein and Nucleic Acid Drug Augment Immunotherapy

Hypoxia severely limits the antitumor immunotherapy for breast cancer. Although efforts to alleviate tumor hypoxia and drug delivery using diverse nanostructures achieve promising results, the creation of a versatile controllable oxygen-releasing nano-platform for co-delivery with immunostimulatory molecules remains a persistent challenge. To address this problem, a versatile oxygen controllable releasing vehicle PFOB@F127@PDA (PFPNPs) is developed, which effectively co-delivered either protein drug lactate oxidase (LOX) or nucleic acids drug unmethylated cytosine-phosphate-guanine oligonucleotide (CpG ODNs). Upon photothermal heating, this platform triggered oxygen release, thereby augmenting LOX-mediated lactate detection rates, and improving T cells infiltrating and cytokine expression. Moreover, under an oxygenated tumor microenvironment (TME), PFPNPs co-delivered with CpG ODNs effectively reprogrammed the immunosuppressive TME by repolarizing macrophages to an M1-like phenotype, promoting dendritic cells maturation, and increasing tumor-infiltrating T cells while decreasing the ratio of regulatory T cells (Tregs). Our study demonstrated that this controlled oxygen-releasing platform possessed adaptive drug-loading capabilities to meet varied immunotherapeutic demands in clinical settings.