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Targeting tumor microenvironment with biomimetic nanovesicles for non-small cell lung cancer gene therapy
Qihang Yan1,2, Li Gong1, Zihui Tan1,2
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
Abstract:
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with therapeutic outcomes often constrained by the complexity of the tumor microenvironment (TME). Comprising diverse cell types and signaling molecules, the TME is increasingly recognized as a critical determinant of tumor behavior and patient prognosis. Cancer-associated fibroblasts (CAFs), a dominant TME component, drive progression through intercellular communication. Although CAF-targeted therapies hold promise, the precise mechanisms underlying CAF-cancer cell interactions remain elusive. Leveraging single-cell sequencing, we identified ACTN1 as a gene highly expressed in CAFs and strongly correlated with NSCLC prognosis. We engineered an integrated hybrid nanovesicle composed of CAF membranes (cM) and a liposome core to encapsulate siRNA against ACTN1 (siACTN1). This represents the first CAF-membrane-coated siRNA system targeting ACTN1 for NSCLC therapy. The nanovesicles modulate cytokine secretion (IL-6 and CCL2) to inhibit NSCLC cell growth, migration, and invasion in vitro. In vivo studies corroborated these findings, demonstrating reduced cytokine secretion and attenuated tumor growth. By harnessing the intrinsic properties of CAFs for targeted siRNA delivery, these nanovesicles offer a novel strategy for TME modulation in NSCLC.
Insights
This study introduces a novel nanovesicle therapy targeting ACTN1 in non-small cell lung cancer (NSCLC). The therapy utilizes cancer-associated fibroblast membranes to deliver siRNA, effectively inhibiting tumor growth and improving prognosis.
Area of Science:
- Oncology
- Nanomedicine
- Cancer Biology
Background:
- Non-small cell lung cancer (NSCLC) is a major cause of cancer mortality.
- The tumor microenvironment (TME) significantly influences NSCLC progression and patient outcomes.
- Cancer-associated fibroblasts (CAFs) are key components of the TME driving tumor growth.
Purpose of the Study:
- To identify novel therapeutic targets within the TME for NSCLC.
- To develop a targeted drug delivery system for NSCLC therapy.
- To investigate the role of ACTN1 in NSCLC and its potential as a therapeutic target.
Main Methods:
- Single-cell sequencing was used to identify ACTN1 as a highly expressed gene in CAFs correlated with NSCLC prognosis.
- An integrated hybrid nanovesicle was engineered using CAF membranes (cM) and a liposome core encapsulating siRNA against ACTN1 (siACTN1).
- In vitro and in vivo studies were conducted to evaluate the efficacy of the siACTN1-loaded nanovesicles.
Main Results:
- ACTN1 was identified as a prognostic marker in NSCLC and highly expressed in CAFs.
- The engineered nanovesicles successfully delivered siACTN1 and modulated cytokine secretion (IL-6 and CCL2).
- In vitro and in vivo experiments demonstrated inhibition of NSCLC cell growth, migration, invasion, and tumor growth.
Conclusions:
- The developed CAF-membrane-coated nanovesicles represent a novel strategy for targeted siRNA delivery in NSCLC.
- This approach offers a promising therapeutic avenue for modulating the TME and improving outcomes for NSCLC patients.
- Targeting ACTN1 via this nanovesicle system demonstrates potential for effective NSCLC treatment.
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