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<p>Non-small cell lung cancer (NSCLC) frequently develops acquired resistance to immune checkpoint inhibitors (ICIs), necessitating innovative strategies to remodel the immunosuppressive tumor microenvironment (TME). This study engineered an inhalable pH-responsive nano-liposome co-delivering Astragaloside IV (AS-IV) and Polyphyllin VII (Pol VII) (AS-IV/Pol VII-Lipo) to overcome anti-PD-1 resistance via spatiotemporal-controlled dual-drug delivery. AS-IV/Pol VII-Lipo (1:1 mass ratio) exhibited optimal physicochemical properties: high drug loading and pH-triggered release. Nebulized inhalation achieved 3.4-fold higher lung accumulation than oral administration. Suppressed orthotopic LLC-Luc tumor growth by 54% and reduced exhausted CD8⁺ T cells while increasing cytotoxic CD8⁺Granzyme B⁺ T cells. Combination therapy further inhibited tumor metastasis and elevated survival. Transcriptomics (RNA-seq) identified suppression of IL-2/STAT5/BLIMP1 pathway and T-cell exhaustion genes. AS-IV/Pol VII-Lipo reprograms the immunosuppressive TME through three synergistic mechanisms: (1) enhanced lung-targeted drug delivery via inhalation; (2) reversal T-cell exhaustion through IL-2/STAT5/BLIMP1 pathway inhibition; (3) synergizing with αPD-1 therapy to overcome ICI resistance. This inhalable nanoplatform presents a promising clinical strategy for NSCLC patients with acquired immunotherapyresistance.</p>

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Inhalable Herbal Nano-Liposomes Co-Delivering Astragaloside IV and Polyphyllin VII Reprogram Immunosuppressive Microenvironment To Overcome Anti-PD-1 Resistance in NSCLC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Yao Liu,
  • Tianqi An,
  • Zujun Que,
  • Bin Luo,
  • Wenfei Shi,
  • Yiyang Zhou,
  • Jianhui Tian

摘要

Non-small cell lung cancer (NSCLC) frequently develops acquired resistance to immune checkpoint inhibitors (ICIs), necessitating innovative strategies to remodel the immunosuppressive tumor microenvironment (TME). This study engineered an inhalable pH-responsive nano-liposome co-delivering Astragaloside IV (AS-IV) and Polyphyllin VII (Pol VII) (AS-IV/Pol VII-Lipo) to overcome anti-PD-1 resistance via spatiotemporal-controlled dual-drug delivery. AS-IV/Pol VII-Lipo (1:1 mass ratio) exhibited optimal physicochemical properties: high drug loading and pH-triggered release. Nebulized inhalation achieved 3.4-fold higher lung accumulation than oral administration. Suppressed orthotopic LLC-Luc tumor growth by 54% and reduced exhausted CD8⁺ T cells while increasing cytotoxic CD8⁺Granzyme B⁺ T cells. Combination therapy further inhibited tumor metastasis and elevated survival. Transcriptomics (RNA-seq) identified suppression of IL-2/STAT5/BLIMP1 pathway and T-cell exhaustion genes. AS-IV/Pol VII-Lipo reprograms the immunosuppressive TME through three synergistic mechanisms: (1) enhanced lung-targeted drug delivery via inhalation; (2) reversal T-cell exhaustion through IL-2/STAT5/BLIMP1 pathway inhibition; (3) synergizing with αPD-1 therapy to overcome ICI resistance. This inhalable nanoplatform presents a promising clinical strategy for NSCLC patients with acquired immunotherapyresistance.