Self-assembling pH-responsive peptide nanoparticles delivering pyrvinium pamoate induce osteosarcoma senescence through CBX4 ubiquitination-mediated inhibition of YAP1 SUMOylation.

Abstract

Osteosarcoma is a highly malignant and metastasis-prone bone tumor, and current treatment options remain unsatisfactory, underscoring the urgent need for new targeted strategies. Induction of cellular senescence represents a promising non-apoptotic antitumor mechanism. Although CK1α is considered to have tumor-suppressive potential, its underlying mechanism and the limited bioavailability of its specific activator pyrvinium pamoate (PP) have hindered clinical translation. Here, we developed a pH-responsive biomineralization-induced peptide self-assembly nanodelivery system (NP@PP) to improve the druggability of PP. Through in vitro and in vivo experiments combined with transcriptomic sequencing, co-immunoprecipitation, and Western blot analysis, we found that PP released from NP@PP efficiently activated CK1α and specifically promoted the ubiquitin-dependent degradation of CBX4. The loss of CBX4 further suppressed YAP1 SUMOylation and blocked its nuclear translocation, thereby activating p16INK4a and p21Cip1 expression, inducing osteosarcoma cell senescence, and inhibiting proliferation and metastasis. In mouse models, NP@PP markedly suppressed xenograft growth and lung metastasis, prolonged survival, and showed no obvious toxicity. These findings reveal a critical role of the CK1α-CBX4-YAP1 signaling axis in senescence-based osteosarcoma therapy and provide a theoretical and practical basis for the development of new nanomedicines.