Remodeling of Mitochondrial Metabolism by a Mitochondria-Targeted RNAi Nanoplatform for Effective Cancer Therapy

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Mitochondrial Medicine

Background:

• Mitochondrial metabolism dysfunction is a key driver of cancer progression.
• Targeting mitochondrial genome (mtDNA)-encoded proteins offers a therapeutic strategy, but delivery into mitochondria is challenging.

Purpose of the Study:

• To develop a mitochondria-targeted RNA interference nanoparticle (NP) platform for breast cancer (BCa) therapy.
• To investigate the efficacy of regulating mitochondrial metabolism and its impact on tumor growth and the tumor microenvironment.

Main Methods:

• Fabrication of a core-shell NP with a polyethylene glycol (PEG) shell and a poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) core.
• Encapsulation of mitochondria-targeting and membrane-penetrating peptide amphiphile (MMPA) and small interfering RNA (siRNA) complexes within the NP core.
• In vitro and in vivo evaluation of NP-mediated siRNA delivery into mitochondria to down-regulate mtDNA-encoded proteins (ATP6, CYB).

Main Results:

• The developed NP platform successfully delivered siRNA into mitochondria, down-regulating ATP6 and CYB expression.
• ATP6 down-regulation suppressed cellular ATP production and increased reactive oxygen species (ROS) generation, leading to mitochondrial damage.
• The released mtDNA from damaged mitochondria reprogrammed tumor-associated macrophages (TAMs) to an anti-tumor M1-like phenotype, combinatorially inhibiting tumor growth.

Conclusions:

• The mitochondria-targeted RNAi NP platform effectively regulates mitochondrial metabolism for breast cancer therapy.
• This approach offers a dual therapeutic strategy by directly inhibiting tumor growth and modulating the tumor immune microenvironment.