posted on 2024-01-03, 16:34authored byWeiji Qin, Lei Qiao, Qian Wang, Min Gao, Man Zhou, Qiuting Sun, Huiru Zhang, Tianhao Yang, Guisong Shan, Wanqing Yao, Xiaoqing Yi, Xiaoyan He
Heterogeneity
of the tumor microenvironment (TME) is primarily
responsible for ineffective tumor treatment and uncontrolled tumor
progression. Pyroptosis-based immunogenic cell death (ICD) therapy
is an ideal strategy to overcome TME heterogeneity and obtain a satisfactory
antitumor effect. However, the efficiency of current pyroptosis therapeutics,
which mainly depends on a single endogenous or exogenous stimulus,
is limited by the intrinsic pathological features of malignant cells.
Thus, it is necessary to develop a synergistic strategy with a high
tumor specificity and modulability. Herein, a synergistic nanoplatform
is constructed by combining a neutrophil camouflaging shell and a
self-synergistic reactive oxygen species (ROS) supplier-loaded polymer.
The covered neutrophil membranes endow the nanoplatform with stealthy
properties and facilitate sufficient tumor accumulation. Under laser
irradiation, the photosensitizer (indocyanine green) exogenously triggers
ROS generation and converts the laser irradiation into heat to upregulate
NAD(P)H:quinone oxidoreductase 1, which further catalyzes β-Lapachone
to self-produce sufficient endogenous ROS, resulting in amplified
ICD outcomes. The results confirm that the continuously amplified
ROS production not only eliminates the primary tumor but also concurrently
enhances gasdermin E-mediated pyroptosis, initiates an ICD cascade,
re-educates the heterogeneous TME, and promotes a systemic immune
response to suppress distant tumors. Overall, this self-synergistic
nanoplatform provides an efficient and durable method for redesigning
the immune system for targeted tumor inhibition.