# Genetically programmable protein-biomineral core-shell nanovectors for enhancing tumor microenvironment-activated chemotherapy

## TL;DR

This paper introduces a new nanocarrier system that improves chemotherapy by targeting tumors more precisely and reducing side effects.

## Contribution

A genetically programmable core-shell nanovector using SELPs and CaP shells for tumor-activated chemotherapy is developed.

## Key findings

- The S2E3i4Y@CaP-DOX nanovectors achieved a 75.9% tumor inhibition rate in 4T1 tumors.
- The CaP shells reduced drug leakage and toxicity during blood circulation.
- The system showed improved tumor targeting and prolonged retention at tumor sites.

## 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.

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