Self-assembling peptide nanoparticles delivering pyrvinium pamoate induce osteosarcoma senescence via CBX4 ubiquitination.

Osteosarcoma (OS) is a highly aggressive and metastasis-prone bone tumor, particularly affecting children and adolescents. Current treatment options, primarily surgery and chemotherapy, often yield unsatisfactory outcomes, especially in metastatic or recurrent cases. This highlights a critical need for novel targeted therapeutic strategies. Inducing cellular senescence, a non-apoptotic antitumor mechanism, holds promise. While CK1α possesses tumor-suppressive potential, its mechanism and the limited bioavailability of its activator, pyrvinium pamoate (PP), have hindered clinical translation.

Researchers developed a pH-responsive biomineralization-induced peptide self-assembly nanodelivery system, termed NP@PP, to enhance the druggability of pyrvinium pamoate. They conducted comprehensive in vitro experiments using osteosarcoma cell lines and in vivo studies in mouse models. The investigation involved transcriptomic sequencing, co-immunoprecipitation, and Western blot analysis to elucidate the molecular mechanisms. Primary endpoints included assessing osteosarcoma cell senescence, proliferation, metastasis, xenograft growth, lung metastasis, and overall survival in the mouse models, with untreated controls for comparison.

The NP@PP system effectively released pyrvinium pamoate, which then efficiently activated CK1α. This activation specifically promoted the ubiquitin-dependent degradation of CBX4. The subsequent loss of CBX4 further suppressed YAP1 SUMOylation, preventing its nuclear translocation. This cascade ultimately activated the expression of p16INK4a and p21Cip1, key markers of cellular senescence. In in vitro settings, these molecular changes led to the induction of osteosarcoma cell senescence and inhibition of proliferation and metastasis.

In mouse models, NP@PP markedly suppressed xenograft growth and lung metastasis, significantly prolonging survival without exhibiting obvious toxicity. These findings collectively reveal a crucial role for the CK1α-CBX4-YAP1 signaling axis in senescence-based osteosarcoma therapy.