摘要
Stimuli-responsive polymeric nanoparticles exhibit as effective vehicles for escorting chemotherapeutic agents and show improved therapeutic efficiency. However, the dense stroma accumulation in the solid tumor impedes the transportation of the drugs into the core region. To address this issue, a tumor-responsive polypeptide nanoparticle with programmable degradation manner is developed in this study for tumor matrix remodeling and enhanced anticancer effect. Two tailor-designed polypeptide sequences are mainly composed of polyCysteine, polyHistidine, and polyLeucine triblocks with distinct functions, including reductive disulfide bonds as protective shell for encapsulated drugs, protonation for the facilitated decomposition of nanoparticles, and hydrophobic complexation domain for nanoparticle self-assembly, respectively. Moreover, tLyP1 serves as an active-targeting ligand toward tumor cells, while polyethylene glycol (PEG) at the corona layer helps reduce reticuloendothelial system (RES) uptake. The results show that multiple sensitive linkages successfully secured drugs from leakage in normal physiological condition and efficiently promoted drug release by endogenous stimuli at tumor site. The nanoparticles exhibit a high selectivity toward specific cell types, depending on the expression level of neuropilin-1 (NRP-1) receptor. The combinational delivery of Doxorubicin and Vismodegib presents a desirable synergistic effect on enhancing drug penetration depth. Also, a declined tendency of Hedgehog signaling-related genes indicates the amelioration of extracellular collagen deposition. Similarly, the therapeutic efficacy is observed in the murine orthotopic breast model. Overall, the programmable dissociation of the self-assembly polypeptide nanoparticles leads to a prominent therapeutic potency on resolving the complexities of solid tumor desmoplasia.