Stimuli-responsive nanoparticles with tailorable elastin-like polypeptide chains for improved brain tumor targeting and therapy.

Glioblastoma (GBM), the most aggressive brain tumor, poses significant therapeutic challenges due to its infiltrative growth, resistance to conventional therapies, and the impermeable blood-brain barrier (BBB), which restricts drug delivery. To address these limitations, we developed a stimuli-responsive nanoplatform based on elastin-like polypeptides (ELPs)-biocompatible, thermally responsive biopolymers that enable precise drug release. The length-variable ELPs endow nanoparticles with tunable physicochemical characteristics, enabling the optimization of delivery efficiency through length-specific selection. By engineering chimeric polypeptide-doxorubicin conjugates (L-CP-DOX NPs) with varying ELP chain lengths (99, 618, and 1200 repeats), we identified L-CP1200-DOX NPs as the optimal formulation, exhibiting enhanced drug encapsulation and superior temperature-responsive controlled release properties. Under the mediation of tumor-penetrating peptide LinTT1, L-CP1200-DOX NPs efficiently traverse the BBB and precisely target tumor tissues. Meanwhile, mild hyperthermia in the tumor microenvironment triggers a phase transition of ELP1200, leading to tumor-specific drug release. In vivo evaluations in orthotopic glioblastoma models demonstrated enhanced tumor accumulation, remarkable antitumor efficacy, and significantly reduced off-target toxicity. This study reveals ELP-based nanocarriers as a versatile platform for thermally responsive brain tumor targeting, underscoring their translational promise in protein-based delivery systems across biomedical fields.