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

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 α_vβ₃ 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 α_vβ₃-expressing cancer cells for improved tumor-targeting and prolonged tumor retention. <i>In vivo</i> 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.