Multifunctional nanoparticles and collagenase dual loaded thermosensitive hydrogel system for enhanced tumor-penetration, reversed immune suppression and photodynamic-immunotherapy.

Breast cancer is the most prevalent and lethal malignancy among females, with a critical need for safer and less invasive treatments. Photodynamic therapy (PDT) can effectively eliminate tumor cells with minimal side effects. Furthermore, the combination of PDT and immunotherapy using nanoparticles has shown promise in treating both primary and distant metastatic tumor cells. Therefore, this study proposes applying the PDT-immunotherapy combination to breast cancer treatment. However, the low immunogenicity characteristic of "cold" tumors in part of breast cancer significantly diminishes therapeutic efficacy. To address this challenge, here, a nano-gel system (designated as HCSC-gel) is constructed, which co-delivers a mitochondria-targeted photosensitizer and a STING agonist, capable of robustly activating "cold" tumor immunity. This system is further enhanced by collagenase (CN) to improve therapeutic outcomes. Upon injection into the primary tumor site, HCSC-gel rapidly forms a gel matrix, releasing CN to degrade the tumor extracellular matrix and facilitate the penetration of photosensitizers, STING agonists, and oxygen into the tumor tissue. Under laser irradiation, PDT and STING-mediated immune responses are activated, reversing the low immunogenicity of breast cancer and effectively treating both primary and metastatic lesions. This HCSC-gel nano hydrogel delivery platform is anticipated to provide novel insights for the clinical management of breast cancer and other low immunogenic "cold" tumors, offering significant benefits to patients.