Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy
Chenglin Liang1, Ge Zhang1, Linlin Guo1
1School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou, 450001, China.
Abstract:
Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy, but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration. Herein, we designed a cancer-associated fibroblasts (CAFs) triggered structure-transformable nano-assembly (HSD-P@V), which can directionally deliver valsartan (Val, CAFs regulator) and doxorubicin (DOX, senescence inducer) to the specific targets. In detail, DOX is conjugated with hyaluronic acid (HA) via diselenide bonds (Se-Se) to form HSD micelles, while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer, which is coated on Val nanocrystals (VNs) surface for improving the stability and achieving responsive release. Once arriving at tumor microenvironment and touching CAFs, HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment. VNs can degrade the extracellular matrix, leading to the enhanced penetration of HSD. HSD targets tumor cells, releases DOX to induce senescence, and recruits effector immune cells. Furthermore, senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy. In vitro and in vivo results show that the nano-assembly remarkably inhibits tumor growth as well as lung metastasis, and extends tumor-bearing mice survival. This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.
Insights
This study introduces a novel nano-assembly that targets cancer-associated fibroblasts to deliver drugs, enhancing anti-tumor immunotherapy by inducing tumor cell senescence and improving immune cell infiltration.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Fibrotic matrix in tumors hinders drug penetration and immune cell infiltration, limiting the efficacy of senescence induction therapy.
- Targeted delivery systems are needed to overcome these barriers and enhance anti-tumor immunotherapy.
Purpose of the Study:
- To design a structure-transformable nano-assembly (HSD-P@V) that is triggered by cancer-associated fibroblasts (CAFs).
- To achieve directional delivery of valsartan (Val) and doxorubicin (DOX) to tumor sites.
- To enhance anti-tumor immunotherapy by inducing tumor cell senescence and promoting immune cell infiltration.
Main Methods:
- DOX was conjugated with hyaluronic acid (HA) via diselenide bonds to form HSD micelles.
- A CAF-sensitive peptide was grafted onto HSD, forming a hydrophilic polymer coated on Val nanocrystals (VNs).
- The nano-assembly (HSD-P@V) was designed to disintegrate upon encountering CAFs, releasing VNs to degrade the extracellular matrix and HSD micelles for DOX delivery.
Main Results:
- The nano-assembly effectively degraded the extracellular matrix, improving drug penetration and immune cell infiltration.
- DOX release induced tumor cell senescence, and recruited immune cells cleared senescent cells.
- In vitro and in vivo studies demonstrated significant inhibition of tumor growth and lung metastasis, with extended survival in tumor-bearing mice.
Conclusions:
- The developed nano-assembly provides a promising strategy for programmed, multi-site nanomedicine delivery in cancer immunotherapy.
- This approach effectively overcomes the limitations of fibrotic tumor microenvironments, enhancing therapeutic outcomes.
