Ultrasound-triggered immunogenic nanotherapeutics for optimizing osteosarcoma therapy by enhancement of tumor microenvironment responsive delivery

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Abstract In osteosarcoma, the efficacy of immune-checkpoint blockade immunotherapy is hindered by low immunogenicity and limited T-cell infiltration and thus, triggering robust antitumor immune responses has become a pivotal goal in cancer therapy. Herein, we design a novel approach to promote immune responses by combining immune checkpoint therapy with a newly developed nanoplatform for sonodynamic therapy. The study involved the attachment of Ce6 photosensitizer to phenylboronic acid -based nanoparticles named Ce6 NPs, which were encapsulated in a hydrogel along with anti-PD-1. As a result, Ce6 NPs@Gel showed active inhibiting tumors in vivo, especially in acidic microenvironments. Upon ultrasound stimulation, the nanoparticles released a large amount of oxygen and damage-associated molecular patterns, triggering immunogenic cell death and enhancing the immunotherapeutic response. This led to an increase in tumor immunogenicity and dendritic cell maturation, ultimately the tumor microenvironment become more infiltrated with cytotoxic T lymphocytes. The Ce6 NPs@Gel formulation demonstrated a significant promotion of immune response and inhibition of tumor growth in mouse models with tumors. This study shows that Ce6 NPs@Gel presents a promising strategy for simultaneous SDT and enhanced immunotherapy against tumors, with potential for clinical translation.

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