Biodegradable polymersomes encapsulating copper peroxide and gemcitabine for targeted chemoimmunotherapy.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Triple-negative breast cancer (TNBC) exhibits resistance to conventional therapies.
• Developing targeted drug delivery systems is crucial for effective cancer treatment.
• Immunotherapy shows promise but faces challenges in overcoming the tumor microenvironment (TME).

Purpose of the Study:

• To engineer ROS-responsive polymersomes (HA-PGC) for targeted TNBC therapy.
• To combine chemodynamic therapy with immunotherapy for enhanced anti-cancer effects.
• To overcome resistance in TNBC by converting cold tumors into hot tumors.

Main Methods:

• Fabrication of hyaluronic acid-functionalized polymersomes (HA-PGC) encapsulating gemcitabine (GEM) and copper peroxide nanoparticles (CuO₂).
• Utilizing CuO₂ decomposition in the acidic TME to generate ROS via Fenton-like reactions.
• Assessing the synergistic effects of ROS on gemcitabine activation, glutathione depletion, and immunogenic cell death (ICD).
• Evaluating the combined efficacy of HA-PGC nanoparticles and anti-PD-L1 immunotherapy in a TNBC model.

Main Results:

• HA-PGC nanoparticles effectively targeted CD44-overexpressing TNBC cells.
• Induced ROS suppressed cytidine deaminase (CDA), enhancing GEM activation, and depleted glutathione (GSH), reducing ROS scavenging.
• Oxidative stress promoted ICD, dendritic cell maturation, and increased tumor-infiltrating lymphocytes.
• The nanoparticle platform converted cold tumors to hot tumors, significantly improving anti-PD-L1 immunotherapy efficacy.

Conclusions:

• A novel multifunctional nanoparticle platform combining chemodynamic therapy and immunotherapy was demonstrated.
• This strategy shows promise for overcoming resistance in triple-negative breast cancer treatment.
• The findings provide a foundation for designing intelligent immunotherapeutic systems.