Mitochondria-Targeted HA-Coated Nanosystem for ROS/CO Generation and Metabolic Reprogramming to Enhance Tumoricidal...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunotherapy

Background:

• Tumor-associated macrophage (TAM) polarization is a key factor in tumor progression and immune evasion.
• Targeting TAMs for repolarization offers a promising strategy for cancer immunotherapy.
• Mitochondrial dysfunction and reactive oxygen species (ROS) production are implicated in TAM polarization.

Purpose of the Study:

• To develop a mitochondria-targeted nanosystem for repolarizing TAMs and enhancing antitumor immunity.
• To investigate the efficacy of the nanosystem in modulating the tumor microenvironment and inhibiting tumor growth.

Main Methods:

• Synthesis of a mitochondria-targeted nanosystem (HA@MR@PCN-CORM) using zirconium-based metal-organic frameworks (PCN-224) loaded with a CO-releasing molecule (CORM-401).
• Surface modification with hyaluronic acid (HA) for CD44 receptor targeting and triphenylphosphine (TPP) for enhanced mitochondrial accumulation.
• In vitro and in vivo evaluation of TAM repolarization, ROS/CO generation, M2-like TAM depletion, and antitumor efficacy.

Main Results:

• The nanosystem efficiently targeted TAM mitochondria, inducing a ROS and CO storm upon laser irradiation, leading to 66.8% M2-like TAM killing.
• Significant repolarization of M1/M2-type TAMs (ratio increased from 0.29 to 1.20) and 93.4% tumor volume inhibition in vivo.
• Enhanced infiltration of cytotoxic T lymphocytes (CD3+/CD4+, CD3+/CD8+) and dendritic cells (DCs) in the tumor tissues.

Conclusions:

• The developed mitochondria-targeted nanosystem effectively depletes and modulates TAMs in an immunosuppressive tumor microenvironment.
• This strategy shows significant potential for enhancing antitumor therapy by reprogramming the tumor immune landscape.