Universal Antibody-Engineered Lipid Nanoparticles Potentiate Chemo-Immunotherapy Against Triple-Negative Breast...

Area of Science:

• Oncology
• Immunology
• Nanotechnology
• Drug Delivery

Background:

• Triple-negative breast cancer (TNBC) treatment is challenged by targeting deficiencies and immune suppression within the tumor microenvironment (TME).
• Existing therapies struggle to overcome T cell exhaustion and the immunosuppressive nature of the TME.

Purpose of the Study:

• To develop a novel drug-encapsulated lipid nanoparticle (LNP) system for enhanced TNBC treatment.
• To reprogram tumor metabolism and reverse immune tolerance by combining chemotherapy and immunotherapy.

Main Methods:

• Developed a targeted LNP system encapsulating monomethyl auristatin E (MA) and metformin (Met).
• Conjugated the LNP to a ROR1 antibody (ROR1 Ab) for active targeting and NIR-II fluorescence imaging.
• Investigated metformin's effect on PD-L1 expression and TGF-β1 levels via mitochondrial oxidative phosphorylation (OXPHOS) inhibition.

Main Results:

• ROR1 Ab-mediated targeting achieved precise tumor localization and enhanced therapeutic efficacy with reduced toxicity.
• Metformin suppressed OXPHOS, leading to decreased PD-L1 and TGF-β1 levels.
• Restored T lymphocyte activity and amplified the anti-tumor immune response.

Conclusions:

• The developed targeted LNP system effectively reprograms tumor metabolism and reverses immune tolerance in TNBC.
• This novel approach demonstrates potential for enhanced TNBC therapy through combined metabolic and immune modulation.