Bola-amphiphilic dendrimers with tunable architecture for ROS-responsive precision delivery of doxorubicin

Stimuli-responsive nanocarriers capable of precise intracellular drug release are critical for improving the efficacy and safety of cancer chemotherapy. However, many existing systems suffer from limited structural tunability and incomplete integration of molecular architecture, self-assembly, and responsiveness, which constrains tumor delivery and therapeutic performance. Here, we report reactive oxygen species (ROS)-responsive bola-amphiphilic dendrimers with tunable dendron generations, bola4A and bola8A, as a platform for doxorubicin (DOX) delivery and systematic comparison. Both dendrimers displayed high drug-loading capacities and stable nanoassembly formation, whereas bola4A, with lower-generation PAMAM dendrons, permitted more efficient stimulus penetration into the nanosystems. This architectural feature enhanced ROS- and pH-triggered drug release, promoted cellular uptake, and accelerated endosomal escape. Importantly, modulation of dendron generation systematically altered nanoparticle architecture and responsiveness, directly dictating therapeutic efficacy. Consequently, bola4A/DOX nanoparticles achieved superior tumor accumulation and tissue penetration, together with improved anticancer efficacy in vitro and in ovarian cancer SKOV3 xenograft models and reduced systemic toxicity relative to free DOX. These results establish dendritic architecture as a key determinant of stimuli-responsiveness and drug delivery performance, and provide a rational framework for the design of next-generation stimuli-responsive nanomedicines tailored to pathological microenvironments.