Carrier-Free Nanoassembly Suppresses Phase Separation via Ribosome-Inspired Crowding Control for Enhanced...

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Chemotherapy's efficacy is limited by immunosuppressive tumor microenvironments, particularly M2-like tumor-associated macrophages (TAMs).
• Modulating mammalian target of rapamycin (mTOR) signaling offers a strategy to repolarize TAMs toward an anti-tumor M1 phenotype.

Purpose of the Study:

• To develop a carrier-free nanoassembly (SOP) for enhanced chemo-immunotherapy by targeting TAMs.
• To investigate the mechanism of SOP in reprogramming the tumor microenvironment via mTOR inhibition and liquid-liquid phase separation (LLPS) suppression.

Main Methods:

• Developed a nanoassembly (SOP) comprising the mTOR inhibitor OSI-027 and the chemotherapeutic SN-38.
• Investigated SOP's tumor accumulation, drug release, and impact on TAM phenotype in various preclinical cancer models.
• Assessed SOP's ability to inhibit mTOR signaling, reduce ribosome abundance, disrupt LLPS, and overcome chemotherapy resistance.

Main Results:

• SOP demonstrated enhanced tumor accumulation compared to free drugs.
• SOP effectively induced tumor cell death and immunogenic responses.
• SOP promoted TAM repolarization from M2 to M1 by inhibiting mTOR and suppressing LLPS, leading to synergistic therapeutic effects.
• SOP suppressed resistance-related gene expression and showed robust efficacy in diverse cancer models.

Conclusions:

• The carrier-free nanoassembly SOP is a potent platform for chemo-immunotherapy.
• SOP reprograms the immunosuppressive tumor microenvironment and overcomes chemotherapy resistance.
• LLPS suppression represents a novel mechanism for TAM regulation in cancer therapy.