Injectable hydrogel coloading photothermal biomimetic nanoparticles combined with zirconium-based MOFs nanoadjuvant for augmenting immunotherapy

Triple-negative breast cancer (TNBC) creates significant challenges in clinical treatment due to its highly aggressive nature, lack of effective therapeutic targets, and high susceptibility to lung metastasis. Herein, an injectable dual-nanoparticle hydrogel platform based on biomimetic hybrid-membrane nanoparticles (cancer cell–macrophage fusion membrane) encapsulating a self-assembled indocyanine green (ICG) nanocore photothermal agent and a zirconium-based metal-organic framework (Zr-MOF) loaded with the immunoadjuvant cytosine–phosphate–guanine oligodeoxynucleotide (CpG) is proposed for combined photothermal therapy (PTT) and immunotherapy to enhance tumor permeability and modulate the immunosuppressive tumor microenvironment (ITME). Under 808 nm NIR irradiation (NIR-I), the nanoparticles achieved efficient photothermal conversion and successfully induced immunogenic cell death (ICD) in vitro. Importantly, CpG@MOF effectively activated the TLR9 signaling pathway, thereby promoting macrophage polarization from the M2 to the M1 phenotype. Meanwhile, damage-associated molecular patterns (DAMPs) released following photothermal treatment effectively recruited mature dendritic cells and further enhanced T-cell activation. Accordingly, a single intratumoral administration of (MPI + CpG@MOF)/CMCS-OHA hydrogel effectively suppressed both the treated primary tumor and the untreated distant tumor in a bilateral subcutaneous 4T1 tumor model. Our findings demonstrate the potential of this nanoparticle–hydrogel platform for overcoming immune barriers and advancing immunotherapy for TNBC.