Transformable Nanoparticle‐Enabled Synergistic Elicitation and Promotion of Immunogenic Cell Death for Triple‐Negative Breast Cancer Immunotherapy

Abstract

Although cisplatin‐based neoadjuvant chemotherapy is an efficient therapy approach for triple‐negative breast cancer (TNBC), it has dismal prognosis and modestly improved survival benefit. Here, a synergistic immunotherapy of TNBC premised on the elicitation and promotion of immunogenic cell death (ICD) response, through a transformable nanoparticle‐enabled approach for contemporaneous delivery of cisplatin, adjudin, and WKYMVm is reported. The nanoparticles can sequentially respond to matrix metalloproteinases‐2, pH, and glutathione to achieve structural transformation with the advantages of optimal size change, efficient drug delivery, and well‐controlled release. Cisplatin and adjudin can synergistically amplify reactive oxygen species (ROS) cascade and eventually increase the formation of hydrogen peroxide and downstream highly toxic ROS like •OH, which can elicit ICD response by mechanisms of endoplasmic reticulum stress, apoptotic cell death, and autophagy. WKYMVm can further promote anti‐TNBC immunity by activation of formyl peptide receptor 1 to build stable interactions between dendritic cells and dying cancer cells. Thus, the nanoparticles achieve significant primary tumor regression and pulmonary metastasis inhibition as well as a remarkable survival benefit, with boosting of the innate and adaptive anti‐TNBC immunity.

Bio-Inspired and Smart Nanoparticles for Triple Negative Breast Cancer Microenvironment

“…A multi stimuli-responsive peptide-based prodrug with structure-transformable characteristics for simultaneous delivery of Pt, adjudin (ADD), and WKYMVm was constructed by Xu et al as a combination of chemo- and immunotherapy [ 73 ]. This SDDS responded well to matrix metalloproteinase-2 (MMP-2), a weakly acidic pH, and glutathione (GSH) to achieve structural transformation with the advantages of efficient and sustained drug delivery.…”

“…Enhanced expression of activated caspase-3 (cas-3), as well as the elevated release of TNF-α and interferon gamma (INF-γ), were documented in response to 3-NPs. In addition, it was observed that mice treated with 3-NPs had a lower amount of vascular endothelial growth factor (VEGF)-positive cells aside from the reduced levels of CD31 and MMP-9, demonstrating the potency of 3-NPs on the adaptive and innate immune system against TNBC and its metastasis [ 73 ]. A similar structural transformability, prolonged retention, and higher tumor accumulation have been shown between 3-NPs and 2-NPs.…”

Enzyme-Responsive Nanoparticles for Anti-tumor Drug Delivery

“…In another case, Zhang et al reported an immunotherapy strategy for triple-negative breast cancer based on enzyme-responsive and structure-transformable nanoparticles, as illustrated in Figure 4A (Xu et al, 2019 ). Firstly, peptides containing anti-tumor agents cisplatin (Pt) and adjudin (ADD) and MMP-2-recognizable sequences were synthesized and then self-assembled into spherical nanoparticles with diameters less than 100 nm.…”

Supramolecular Immunotherapy of Cancer Based on the Self‐Assembling Peptide Design

“…[66] For example, Zhang and co-workers developed a transformable nanoparticle for the treatment of triple-negative breast cancer (TNBC) that were formed by the self-assembly of cisplatin, adjudin (ADD), and WKYMVm. [67] Two kinds of peptide-based spherical nanoparticles were designed to deliver Pt and ADD using FFKPt-2TPA-ADDPMGMRGGGG and (2-Nap)-FFKPt-2TPA-ADDPLGVRGGGG. In the two nanoparticles, which had the sequence of (2-Nap)-FFKPt-2TPA-ADDPLGVRGGGG, they can respond to the overexpressed matrix MMP-2 due to the peptide sequence PLGVRG.…”