Modulation of intracellular transport pathways to enhance the transcytosis of nanodrugs across the blood-brain barrier

Effective treatment of brain diseases is limited by poor blood-brain barrier (BBB) penetration of drugs and their nanosized carriers. The intracellular transport of nanocarriers in brain microvessel endothelial cells (BMECs) significantly affects BBB-crossing efficiency. Most nanocarriers follow the lysosomal degradation pathway, where they are trapped and degraded, limiting BBB penetration. Here, we develop spherical nucleic acids (SNAs)-based nanocarriers that enhance BBB traversal by redirecting intracellular transport in BMECs from lysosomal degradation pathway to recycling pathway. A hydrophobic redox-responsive paclitaxel (PTX) prodrug is covalently linked to a hydrophilic nucleic acid complex formed by connecting antisense oligonucleotides targeting survivin mRNA and siRNA targeting Rab7 via a DNA bridge. This produces an amphiphilic conjugate capable of self-assembling into SNAs. These SNAs enter BMECs via scavenger receptors and release siRNA, which reduces Rab7 expression and lysosome formation. Upon re-administration, SNAs are mainly transported through the recycling pathway rather than lysosomal degradation pathway, enhancing BBB crossing and tumor accumulation. High glutathione levels in tumor cells trigger the release of PTX and antisense oligonucleotides, enabling synergistic therapy of glioma. Our strategy addresses the challenge of limited BBB transcytosis and holds promise for improving drug delivery in neurological disorders.