Combination Chemical and Mechanical Tumor Immunomodulation Using Cavitating Mesoporous Silica Nanoparticles.

Combinatorial methods to repolarize tumor-associated macrophages from anti-inflammatory to pro-inflammatory phenotypes offers a promising route for cancer immunotherapy. However, most studies examine biochemical combinations alone. Therefore, we studied simultaneous chemical and mechanical stimuli as orthogonal cues for enhanced immunomodulation. We engineered the surfaces of hydrophobically functionalized mesoporous silica nanoparticles (F108-hMSNs) to encapsulate the immunomodulator resiquimod and kill cancer cells through high-intensity focused ultrasound (HIFU)-mediated inertial cavitation, releasing damage-associated molecular patterns (DAMPs) for prolonged macrophage stimulation. The HIFU doses alone did not affect cells, but in combination with F108-hMSNs, achieved significantly higher cancer cell death and DAMP generation. Inflammatory markers (CD86, MHC II, iNOS) were upregulated in tumor-associated-like macrophages treated with F108-hMSNs in the presence of HIFU and experienced the greatest inflammatory phenotypic shift of all conditions tested. This work suggests that chemical and mechanical activation facilitated by engineered nanoparticles offer a promising treatment against immunologically cold tumors.