The clinical application of natural compounds is limited by their inherent physical and chemical properties. This research reports a hierarchical supramolecular engineering strategy for constructing a dual-assembled nanosystem to treat skin pigmentation. Through artificial intelligence-assisted computational screening of models, tranexamic acid was determined to be a suitable molecular partner for the hydrophobic and active Scutellaria baicalensis. Subsequently, the dual reassembly process produced a stable mixed nanoplatform (DHBTC), which increased the solubility and delivery efficiency of barpicin. Single-cell transcriptomics revealed an unexpected "functional inhibition" mechanism. Although DHBTC has a depigmenting effect, the gene network related to melanin production in melanocytes was upregulated. This reaction was identified as a compensatory transcriptional feedback triggered by drug-induced autophagy. DHBTC functionally inhibits pigment accumulation by accelerating melanosome degradation, thereby causing poor transcriptional activation effect when the cells attempt to restore homeostasis. Additionally, this platform reshapes the skin immune microenvironment into an anti-inflammatory state. This study proposes a strategy for designing drug delivery systems, from computational prediction to supramolecular assembly, and describes a therapeutic mechanism based on regulating post-translational and organelle homeostasis. This study was published in Bioactive Materials under the title "An AI-assisted designed supramolecularly engineered nanoplatform reverses pigmentation by triggering an ineffective compensatory melanin production program".
Reference News: DOI: 10.1016/j.bioactmat.2026.01.027