Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunotherapy

Background:

• Combination therapy is crucial for enhancing anti-tumor responses in cancer immunotherapy.
• Functional nanomaterials enable controlled drug delivery, improving bioavailability and reducing side effects.

Purpose of the Study:

• To design a peptide-assembling nanoparticle for sequential, dual-stimuli-responsive, tumor-targeted delivery of a programmed cell death-ligand 1 (PD-L1) antagonist (d-peptide antagonist of programmed cell death-ligand 1, D PPA-1) and an idoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919).
• To investigate the efficacy of this nanoformulation in inhibiting melanoma growth by concurrently blocking immune checkpoints and tryptophan metabolism.

Main Methods:

• Synthesized an amphiphilic peptide containing 3-diethylaminopropyl isothiocyanate (DEAP), a matrix metalloproteinase-2 (MMP-2) substrate, and D PPA-1.
• Coassembled the peptide with NLG919 into nanoparticles that respond to tumor extracellular matrix stimuli (weak acidity and MMP-2 expression).
• Evaluated the nanoparticles' drug release, tumor cell infiltration, and anti-melanoma effects in vivo.

Main Results:

• The nanoparticles exhibited sequential swelling in acidic tumor environments and collapse upon MMP-2 cleavage, enabling on-demand drug release.
• Concurrent blockade of PD-L1 and IDO pathways significantly increased tumor-infiltrated cytotoxic T cells.
• The nanoformulation effectively inhibited melanoma growth and improved overall survival.

Conclusions:

• Functional peptide-assembling nanoparticles offer a promising platform for dual-targeted cancer immunotherapy.
• Sequential responsiveness to tumor microenvironment hallmarks allows for precise drug delivery and enhanced therapeutic outcomes.
• This approach provides new strategies for developing advanced cancer nanomedicines.