A computer-aided, carrier-free drug delivery system with enhanced cytotoxicity and biocompatibility: A universal model for multifunctional lung cancer therapy.

Erlotinib (ERL) is a first-line targeted therapy for patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC). However, its effectiveness is hindered by acquired resistance and poor bioavailability. Carrier-free nanodrugs are a research hotspot due to their efficient targeting, high drug loading capacity, and the absence of any excipients. Herein, we report an advanced self-delivery system for multimodal NSCLC therapy using a computer-aided strategy. First, we developed a novel heterodimer, ERL-SS-QM (ERL conjugated with QM-OH-a hydrophobic aggregation-induced emission fluorophore-via a disulfide bond [SS]), which serves as both cargo and carrier material. Self-assembly is driven by multiple noncovalent interactions, including π-π stacking and sulfur bonds. Subsequently, an ERL-SS-QM-based "triadic" drug delivery nanoplatform comprising 21 variants was developed. A case study on ursolic acid (UA)-loaded ERL-SS-QM nanoparticles (named UA@ERL-SS-QM NPs) revealed narrow size distribution, small particle size, and well stabilized (zeta potential = -28.9 mV). The UA@ERL-SS-QM NPs demonstrated concentration-dependent toxicity against targeted A549 cells (IC50 = 4.36 μM), outperforming free monomeric drugs ERL (IC50 = 12.94 μM) and UA (IC50 = 12.21 μM), indicating good efficiency. Conversely, these NPs exhibited minimal cytotoxicity in non-targeted BEAS-2B cells, suggesting favorable biocompatibility. Upon endocytosis and interaction with overexpressed GSH in A549 cells, the disulfide-bond linker is cleaved to release three components: ERL, UA (which downregulates β-catenin/TCF4/CT45A2 signaling pathways, inducing apoptosis in ERL-resistant L858R/T790M mutant cells-a key factor in acquired resistance to ERL treatment), and QM-OH. Hence, this work provides a universal model for multifunctional NSCLC therapy that effectively addresses ERL resistance while enhancing cytotoxicity and biocompatibility.