PDL1/HER2‐Targeted Lipid‐Encapsulated Oxygen Nanobubbles Combined with Photodynamic Therapy for HER2+ Breast Cancer Immunotherapy

Abstract Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2‐positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen‐enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid‐encapsulated oxygen nanobubbles (Lipo‐NBs‐O 2 ) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual‐receptor targeted Lipo‐NBs‐O 2 (DRT@Lipo‐NBs‐O 2 ) is prepared by modifying Lipo‐NBs‐O 2 with anti‐PDL1 scFv and the fusion protein anti‐HER2 scFv‐tandem‐repeat cytochrome c (anti‐HER2‐nCyt c ). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo‐PS‐NBs‐O 2 plus near‐infrared irradiation leads to robust ICD induction, increasing DC activation and CD8 + T‐cell numbers. Modification with anti‐PDL1 scFv improves tumor distribution of DRT@Lipo‐PS‐NBs‐O 2 and plays the ICI role, invigorating CD8 + T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo‐PS‐NBs‐O 2 reduces P‐glycoprotein expression. Enhanced PDT and Cyt c can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo‐NBs‐O 2 affords a combination of oxygen delivery and multidrug therapy to alleviate HER2‐positive breast cancer.