Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment

Area of Science:

• Biomedical Engineering
• Immunology
• Oncology

Background:

• Immune checkpoint blockade (ICB) therapy has transformed cancer treatment but faces challenges with T effector cell infiltration and immunosuppressive tumor microenvironments (TME).
• Overcoming these limitations is crucial for improving ICB therapy's clinical success.

Purpose of the Study:

• To develop a programmable bispecific nano-immunoengager (NIE) designed to enhance ICB therapy by improving T effector cell delivery and function within the TME.
• To investigate the in situ structural transformation and therapeutic efficacy of the NIE in preclinical cancer models.

Main Methods:

• Engineered peptidic nanoparticles (NIE-NPs) that transform into nanofibrillar networks (NIE-NFs) within the TME.
• NIE-NFs were designed to bind tumor cells via α₃β₁ integrin and capture T effector cells through an activatable α₄β₁ integrin ligand.
• Sustained release of resiquimod for immunomodulation was incorporated into the NIE-NFs.
• Therapeutic efficacy was evaluated in syngeneic 4T1 breast cancer and Lewis lung cancer mouse models, in combination with anti-PD-1 antibody.

Main Results:

• The bispecific NIE demonstrated in situ structural transformation from nanoparticles to nanofibrillar networks in the TME.
• The NIE successfully captured T effector cells and facilitated their infiltration.
• Combined treatment with the NIE and anti-PD-1 antibody led to the elimination of 4T1 breast cancer and Lewis lung cancer in mice.
• The engineered system showed sustained release of resiquimod, contributing to immunomodulation.

Conclusions:

• The in vivo structural transformation-based supramolecular bispecific NIE is a novel class of programmable, receptor-mediated targeted immunotherapeutics.
• This NIE system effectively enhances ICB therapy by overcoming T cell infiltration barriers and modulating the TME.
• The findings suggest a promising strategy for improving the efficacy of cancer immunotherapy.