PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1
Li Du1,2, Yao Gong1, Xiaoying Zhang1
1The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Background:
PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems.
Results:
We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity.
Conclusions:
In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors.
Insights
This study introduces a novel nanoplatform combining neutrophil elastase and PD-L1 siRNA to enhance anti-tumor immunity and drug delivery for solid tumors, showing significant potential in preclinical models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Immunotherapy
Background:
- Programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) blockade is a key cancer therapy, but limited efficacy is observed due to low tumor immunogenicity and poor drug penetration.
- Neutrophil elastase can enhance tumor immunogenicity, but its therapeutic application is hindered by insufficient enzymatic activity at tumor sites.
Purpose of the Study:
- To design a novel nanoplatform, polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1 small interfering RNA (siRNA), to improve enzymatic activity and enhance siRNA delivery for cancer treatment.
- To evaluate the efficacy of this nanoplatform in stimulating anti-tumor immunity and overcoming resistance to PD-1/PD-L1 blockade.
Main Methods:
- Synthesis of PEI-elastase with enhanced enzymatic activity and gene delivery capabilities.
- Encapsulation of PEI-elastase and PD-L1 siRNA into pH-responsive anionic liposomes to form an anti-tumor lipopolymer (P-E/S Lip).
- Administration of P-E/S Lip in preclinical models to assess tumor killing, immunogenicity, PD-L1 expression reduction, and systemic anti-tumor effects.
Main Results:
- PEI-elastase demonstrated high enzymatic activity and efficient gene delivery.
- P-E/S Lip effectively released its payload in the acidic tumor microenvironment, leading to enhanced tumor immunogenicity and reduced PD-L1 expression.
- Treatment with P-E/S Lip in orthotopic and subcutaneous tumor models significantly inhibited tumor growth, reduced metastasis, and induced systemic anti-tumor responses with minimal toxicity.
Conclusions:
- A protease-based nanoplatform (P-E/S Lip) was developed to synergistically enhance tumor immunogenicity and downregulate PD-L1 expression.
- This approach shows significant potential as a combination therapy for effectively treating solid tumors.
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