A biomimetic oxygen-generating nanoplatform for enhanced sonodynamic immune activation

Background Sonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, its therapeutic efficacy is significantly limited by the hypoxic tumor microenvironment, particularly in breast cancer. To address this limitation, we developed a biomimetic nanoplatform capable of generating oxygen within the tumor microenvironment to enhance SDT performance. Methods Poly (lactic-co-glycolic acid) (PLGA) nanoparticles were co-loaded with catalase and the sonosensitizer IR780 and subsequently coated with 4T1 cancer cell membranes (CIP@4T1m NPs). A series of in vitro and in vivo experiments were conducted to evaluate tumor-targeting capability, hypoxia alleviation, singlet oxygen ( ¹ O ₂ ) generation, antitumor efficacy, induction of immunogenic cell death (ICD), and activation of antitumor immune responses. Results The resulting CIP@4T1m NPs were successfully fabricated and exhibited preferential accumulation in 4T1 tumor cells and orthotopic 4T1 tumor-bearing mice. Both in vitro and in vivo studies demonstrated that the nanoplatform partially relieved tumor hypoxia and significantly enhanced SDT-mediated ¹ O ₂ production and antitumor effects. Moreover, CIP@4T1m NPs combined with ultrasound induced ICD-associated changes, promoted dendritic cell maturation, facilitated the polarization of tumor-associated macrophages from the M2 to M1 phenotype, reduced regulatory T cell populations, and increased intratumoral CD8 ⁺ T-cell infiltration. Conclusion This work describes a biomimetic nanoplatform that integrates homologous targeting with enzymatic oxygen generation to enhance SDT efficacy and promote antitumor immune responses in an orthotopic 4T1 breast cancer model. The proposed strategy offers a potential approach to mitigate hypoxia-associated limitations in cancer therapy.