Reengineered Albumin-Paclitaxel Nanoparticles Remodeling Tumor Cell Death Pathways for Prevention of Chemotherapy-Induced Breast Cancer Metastasis
Time：2026/5/7 22:30:57 Views：126
Triple-negative breast
cancer (TNBC) represents a formidable clinical challenge due to its poor
prognosis and high metastatic propensity. Although paclitaxel chemotherapy
remains a cornerstone of treatment, it can paradoxically promote metastasis by
facilitating Padi4-mediated nuclear expulsion and activating the RAGE/ERK
pathway. In this study, we engineered a tumor-responsive nanoparticle platform
(RAPG) capable of co-delivering paclitaxel, the Padi4 inhibitor GSK484, and a
RAGE antagonist peptide (RAP). RAPG nanoparticles exhibited redox-sensitive
drug release, precise tumor localization, and deep tissue permeation.
Mechanistically, RAPG suppressed histone citrullination, impeded RAGE/ERK
signaling, and reinforced conventional apoptotic pathways, thereby
significantly attenuating tumor invasion and metastasis. This study presents a
promising strategy to counteract chemotherapy-induced metastasis in TNBC
through concurrent inhibition of Padi4-mediated histone citrullination and
RAGE/ERK signaling. The findings have been published in the internationally
renowned journal ACS Nano under the title "Reengineered
Albumin-Paclitaxel Nanoparticles Remodeling Tumor Cell Death Pathways for
Prevention of Chemotherapy-Induced Breast Cancer Metastasis."
TNBC accounts for
approximately 15–20% of all breast cancer cases. The absence of well-defined
therapeutic targets contributes to elevated rates of early recurrence and
distant metastasis. Metastasis is the leading cause of mortality in TNBC
patients: roughly 46% develop distant metastases, and the median overall
survival following metastatic progression is only 13.3 months. While
chemotherapy can induce apoptosis in tumor cells, recent studies have revealed
that chemotherapy-induced apoptosis triggers the release of chromatin-rich
nuclear expulsion products (NEPs) through a Padi4-mediated nuclear expulsion
process. S100a4, which is enriched in these NEPs, binds to RAGE receptors on
neighboring tumor cells and activates the MAPK (ERK1/2) signaling pathway,
thereby promoting tumor metastasis. Clinical data indicate that high Padi4
expression is closely associated with poor prognosis in basal-like breast
cancer patients, and that both Padi4 and RAGE are expressed at higher levels in
metastatic lesions than in primary tumors. Importantly, our analysis of
clinical specimens demonstrated that citrullinated histone H3 (cit H3) and
phosphorylated ERK (p-ERK) levels are significantly elevated in tumor tissues
from TNBC patients receiving paclitaxel chemotherapy, suggesting that
chemotherapy itself may activate this pro-metastatic pathway.
To address these
clinical challenges, we developed a tumor microenvironment-responsive
nano-delivery platform (RAPG). The system is based on disulfide
bond-crosslinked albumin nanoparticles co-loaded with paclitaxel and the Padi4
inhibitor GSK484. The nanoparticle surface is decorated with a RAGE antagonist
peptide (RAP), which undergoes responsive shedding in the presence of matrix
metalloproteinase-2 (MMP-2)—highly expressed in the tumor
microenvironment—thereby inhibiting the RAGE–MAPK axis. Upon cellular
internalization, the elevated intracellular glutathione (GSH) concentration in
tumor cells cleaves the disulfide bonds, triggering the synchronized release of
paclitaxel and GSK484. This dual-drug release mechanism effectively suppresses
Padi4 activity, prevents NEP release and subsequent RAGE activation, and
remodels nuclear expulsion-based tumor cell death into conventional apoptotic
pathways. Both in vitro and in vivo studies demonstrated that RAPG
significantly suppressed the expression of epithelial–mesenchymal transition
markers, reduced tumor invasiveness, circulating tumor cells, and pulmonary
metastasis, while enhancing therapeutic efficacy and prolonging survival.
Ph.D. candidate Liu Bing
is the first author of this paper, and Professor Jiang Chen is the
corresponding author. This research was supported by the National Natural
Science Foundation of China, the Shanghai Municipal Science and Technology
Major Project, the open funding from Pingyuan Laboratory, and the ZJLab.
Original article: https://doi.org/10.1021/acsnano.6c06136
