Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to its aggressive nature and lack of targeted treatments.
• The tumor microenvironment (TME) in TNBC is often immunosuppressive, hindering effective anti-tumor immune responses.
• Nanoparticle-based strategies offer promise for simultaneously modulating the TME and stimulating anti-cancer immunity.

Purpose of the Study:

• To design and evaluate novel nanoparticle-based therapeutic systems for inhibiting TNBC.
• To investigate the potential of dual-drug loaded nanoparticles and biomimetic nanosystems in remodeling the TME and activating anti-tumor immunity.
• To assess the synergistic therapeutic effects of these nanodelivery systems in preclinical TNBC models.

Main Methods:

• Development of chondroitin sulfate (CS)-based nanoparticles co-loading a bromodomain-containing protein 4 (BRD4) inhibitor (JQ1) and a cyclooxygenase-2 (COX-2) inhibitor (celecoxib, CXB) - CS@JQ1/CXB NPs.
• Preparation of a biomimetic nanosystem (MM@P3) by coating self-assembled poly(β-amino ester) nanoparticles with melittin-embedded macrophage membranes (MM).
• In vitro and in vivo evaluation of nanoparticle immune activation efficiencies, synergistic cytotoxicity, anti-migration, apoptosis induction, tumor growth suppression, and metastasis inhibition in TNBC models.

Main Results:

• Both CS@JQ1/CXB and MM@P3 nanoparticles demonstrated high immune activation efficiencies in vitro and in vivo.
• Combination treatment with the nanoparticles exhibited synergistic cytotoxicity, anti-migration, and apoptosis-inducing effects on TNBC cells.
• The combinatorial therapy effectively suppressed tumor growth and metastasis in TNBC-bearing mice, attributed to enhanced tumor immune response and inhibited angiogenesis.

Conclusions:

• The developed CS@JQ1/CXB and MM@P3 nanoparticles represent promising therapeutic strategies for TNBC.
• Simultaneous remodeling of the immunosuppressive TME and immune activation via these nanodelivery systems can overcome therapeutic limitations in TNBC.
• This study presents a novel combinatorial immunotherapeutic approach with potential for clinical translation in TNBC treatment.