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Genetically programmable protein-biomineral core-shell nanovectors for enhancing tumor microenvironment-activated
Kaiyue Zhang1, Xincheng Sun1, Ting Ji1
1Centre for Regeneration and Cell Therapy, The Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China.
Abstract:
Limited chemotherapy efficacy results in frequent treatment failure events in multiple malignant tumors. Because of limited aqueous solubility, short retention time in the tumor, lack of selectivity toward cancerous cells and non-specific toxicity, there is urgent demand for the discovery of innovative cancer drugs with improved efficacy and selectivity. While nanotechnology offers promising solutions for drug delivery, many nanocarriers still face challenges such as premature drug leakage during circulation, insufficient tumor-specific accumulation, and potential off-target toxicity. To address these limitations, we utilize genetically engineered silk-elastin-like proteins (SELPs) as potent tumor-responsive drug carriers. Tumor cells αvβ3 receptor-specific internalizing RGD peptide (iRGD) was encoded into amphiphilic SELP sequences (S2E3i4Y) to form cancer-selective nanoparticles. To minimize the nonspecific uptake and reduce the leakage of loaded doxorubicin (DOX) during blood circulation, calcium phosphate (CaP) shells were fabricated to be the encapsulation layer of the S2E3i4Y-DOX nanoparticles (S2E3i4Y@CaP-DOX), which prevented premature drug leakage, enhanced the therapeutic safety, and minimized toxicity associated with nonspecific delivery. Meanwhile, the acidic-sensitive CaP shells can be decomposed specifically at the tumor sites, initiating the inner S2E3i4Y-DOX couple to αvβ3-expressing cancer cells for improved tumor-targeting and prolonged tumor retention. In vivo assays revealed that S2E3i4Y@CaP-DOX successfully achieved an impressive 4T1 tumor inhibition rate of 75.9 %, much higher than free DOX, without side effects. This core-shell SELP-based platform provides a biocompatible, efficient, and sustainable nanoplatform for tumor-responsive drug delivery, offering a promising strategy for enhanced cancer therapy with spatiotemporal precision.
Insights
Engineered silk-elastin-like protein nanoparticles with calcium phosphate shells effectively deliver doxorubicin, significantly inhibiting tumor growth and reducing side effects for improved cancer therapy.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cancer Therapeutics
Background:
- Chemotherapy faces limitations including poor efficacy, low selectivity, and toxicity due to poor drug solubility and retention.
- Existing nanocarriers struggle with premature drug leakage, insufficient tumor accumulation, and off-target toxicity.
- There is a critical need for advanced drug delivery systems offering enhanced efficacy and selectivity in cancer treatment.
Purpose of the Study:
- To develop a tumor-responsive nanocarrier using genetically engineered silk-elastin-like proteins (SELPs) for improved cancer drug delivery.
- To enhance the stability and tumor-targeting capabilities of doxorubicin (DOX) loaded nanoparticles.
- To evaluate the therapeutic efficacy and safety of the novel nanocarrier system in preclinical cancer models.
Main Methods:
- Genetically engineered amphiphilic SELP sequences (S2E3i4Y) incorporating an iRGD peptide for tumor cell targeting.
- Fabrication of calcium phosphate (CaP) shells around S2E3i4Y-DOX nanoparticles (S2E3i4Y@CaP-DOX) to prevent premature drug leakage.
- In vivo evaluation of the S2E3i4Y@CaP-DOX system in a 4T1 tumor model.
Main Results:
- The S2E3i4Y@CaP-DOX nanoparticles demonstrated controlled doxorubicin release triggered by the acidic tumor microenvironment.
- The nanocarrier system exhibited enhanced tumor-specific accumulation and prolonged retention compared to free doxorubicin.
- Significant tumor inhibition (75.9%) was achieved with the S2E3i4Y@CaP-DOX system in the 4T1 model, with no observed side effects.
Conclusions:
- The core-shell SELP-based nanoplatform (S2E3i4Y@CaP-DOX) offers a biocompatible and efficient approach for tumor-responsive drug delivery.
- This novel system overcomes limitations of traditional chemotherapy and existing nanocarriers, improving therapeutic safety and efficacy.
- The developed nanoplatform presents a promising strategy for precise and enhanced cancer therapy.
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