An Orthogonally Clickable and Stimuli-Responsive Poly(β-amino ester) for the Co-delivery of Doxorubicin and BCL-2 siRNA

A potent drug delivery system (DDS) based on poly(β-amino ester)s (pBAEs) to tackle multidrug resistance (MDR) in lung cancer by codelivering siRNA targeting antiapoptotic BCL-2 and doxorubicin (DOX) has been prepared. Engineered via strain-promoted azide-alkyne cycloaddition (SPAAC) to attach a tripeptide end-chain moiety and thiol-disulfide exchange to conjugate DOX, the system employs a hydrazone linker for dual pH- and redox-responsive release. This ensures precise tumor targeting with minimal leakage in the circulation. In multidrug-resistant lung cancer cells (GLC-4/ADR), it sharply downregulates BCL-2 expression, amplifying DOX’s therapeutic impact.