Engineered charge adaptive nanoplatform overcomes the drug penetration barriers to potentiate the efficacy of chemotherapy.

Breast cancer continues to present a major clinical hurdle, largely attributable to its aggressive metastatic behavior and the suboptimal efficacy of standard chemotherapeutic regimens. Cisplatin (CDDP) is a representative platinum drug in the treatment of breast cancer, however, its therapeutic application is often constrained by systemic toxicity and the frequent onset of chemoresistance. Here, we introduce a novel charge-adaptive nanoprodrug system, referred to as PP@, engineered to respond to tumor-specific conditions. This platform was constructed by conjugating ibuprofen and polyethylene glycol (PEG) to the hydrophobic and hydrophilic termini of an amphiphilic dendrimer, respectively, enabling the formation of uniform and stable nanostructures through spontaneous self-assembly. Importantly, PP@ undergoes charge reversal in response to acidic pH and elevated glutathione levels (GSH), facilitating deeper tumor penetration. Cisplatin was subsequently encapsulated within the nanoprodrug to yield the PP@-based CDDP nanoformulation (PP@CDDP). The physicochemical properties and therapeutic performance of PP@CDDP were systematically evaluated. The results demonstrated that PP@CDDP significantly improves cellular uptake, suppresses drug efflux, and reduces intracellular GSH levels, collectively contributing to prolonged drug retention at the tumor site. In vivo studies further confirmed that PP@CDDP significantly improved the antitumor efficacy of cisplatin, as evidenced by marked inhibition of tumor growth and metastasis, along with a favorable safety profile. These results underscore the potential of this charge-adaptive nanoprodrug platform to address key limitations of traditional cisplatin chemotherapy. The rational integration of smart material design with pharmacological strategies offers a promising pathway for improving therapeutic outcomes in cancer treatment.