Combination Chemical and Mechanical Tumor Immunomodulation Using Cavitating Mesoporous Silica Nanoparticles

Area of Science:

• Biomedical Engineering
• Cancer Immunology
• Nanotechnology

Background:

• Tumor-associated macrophages (TAMs) often exhibit an anti-inflammatory phenotype, hindering anti-tumor immune responses.
• Repolarizing TAMs to a pro-inflammatory phenotype is a key strategy in cancer immunotherapy.
• Current approaches primarily focus on biochemical stimuli, limiting therapeutic efficacy.

Purpose of the Study:

• To investigate the synergistic effects of simultaneous chemical and mechanical stimuli for enhanced immunomodulation.
• To engineer nanoparticles capable of delivering immunomodulators and generating damage-associated molecular patterns (DAMPs).
• To assess the efficacy of this combined approach in repolarizing TAMs and promoting anti-tumor immunity.

Main Methods:

• Engineered hydrophobically functionalized mesoporous silica nanoparticles (F108-hMSNs) to encapsulate resiquimod.
• Utilized high-intensity focused ultrasound (HIFU)-mediated inertial cavitation to induce cancer cell death and DAMP release.
• Co-administered F108-hMSNs and HIFU to stimulate TAMs and evaluate phenotypic shifts.

Main Results:

• HIFU combined with F108-hMSNs significantly increased cancer cell death and DAMP generation compared to HIFU alone.
• Treatment with F108-hMSNs and HIFU led to upregulation of inflammatory markers (CD86, MHC II, iNOS) in TAMs.
• The combined approach induced the most significant inflammatory phenotypic shift in TAMs among all tested conditions.

Conclusions:

• Simultaneous chemical and mechanical activation using engineered nanoparticles and HIFU is a potent strategy for TAM repolarization.
• This combinatorial approach shows promise for overcoming immune suppression in immunologically "cold" tumors.
• Further development of such dual-stimuli strategies could advance cancer immunotherapy.