Engineering nanoparticles boost TNBC therapy by CD24 blockade and mitochondrial dynamics regulation

Area of Science:

• Oncology
• Immunology
• Nanotechnology

Background:

• Triple-negative breast cancer (TNBC) treatment remains challenging due to low immunogenicity and immunosuppressive tumor microenvironments.
• Existing immunotherapies face limitations in effectively treating TNBC.

Purpose of the Study:

• To engineer nanoparticles delivering anti-CD24 antibody, celastrol, and shMFN1 for synergistic TNBC treatment.
• To enhance tumor cell immunogenicity and modulate tumor-associated macrophages (TAMs) for improved immunotherapy.

Main Methods:

• Nanoparticles (P-aCD24/CEL + P/shMFN1) designed for dual targeting of tumor cells and TAMs.
• Utilized pH and MMP2-responsive release of anti-CD24 and celastrol (CEL) to induce immunogenic cell death (ICD).
• Employed shMFN1 delivered via nanoparticles to TAMs for M2 phenotype reversal via MFN1 silencing.

Main Results:

• Engineered nanoparticles successfully delivered therapeutic agents, enhancing tumor cell phagocytosis by macrophages.
• Celastrol induced ICD and reduced CD24 expression, while shMFN1 reversed M2-TAM phenotype.
• Combination therapy demonstrated significant inhibition of tumor growth and recurrence, establishing long-term immune memory.

Conclusions:

• The combination immunotherapy strategy effectively remodels the immunosuppressive tumor microenvironment in TNBC.
• This approach holds significant potential for advancing TNBC treatment by enhancing antitumor immune responses.