Tumor Mechanobiology-Inspired Nanomechanics: Piezo1 Mediated Tumor-Associated Macrophages Reprogramming and Exosome-Driven Immune Amplification

Mechanosensitive signaling pathways in immune cells drive exhaustion and ultimately facilitate tumor immune escape. In situ mechanical modulation strategies, leveraging the tumor's mechanical features, may provide a distinctive perspective for immunotherapy. We repurpose conventional silica nanocarriers from mere "drug delivery vehicles" into "Piezo1 mechanotransduction modulators" by precisely tuning their mechanical properties to directly intervene in tumor-associated macrophages (TAMs) mechanosignaling. Our study revealed that Piezo1 acts as a mechano-immunological switch in tumors: its downregulation in large tumors promotes M2-like TAMs polarization, whereas its upregulation in small tumors drives M1-mediated antitumor immunity. This directly couples mechanical cues to immune reprogramming during Cancer progression. To target this pathway, we engineered mesoporous silica nanoparticles (mSNs) with tunable stiffness (253-1084.5 MPa), which were loaded with the Piezo1 agonist Yoda1 and TAMs-targeting peptide CRV (YmSNs@CRV) to precisely modulate TAMs mechanosignaling. Results demonstrated that softer 20% mSN achieved dual regulation of both macrophage phenotypic reprogramming and exosome-mediated communication via Piezo1 activation. Specifically, softer 20% mSNs enhanced pro-inflammatory markers (CD80), increased cytokine secretion, and promoted exosome production 5-fold more effectively than stiffer 80% mSNs. Proteomic analysis revealed that exosomes from 20% mSN-treated macrophages activated the TCR signaling, amplifying immune responses. In vivo, 20% YmSNs@CRV improved tumor penetration, repolarized TAMs toward an antitumor phenotype, and boosted cytotoxic T cell infiltration, significantly inhibiting tumor growth. This study integrates the mechanical characteristics of tumor tissues and proposes an "in situ mechanical dual-regulation" strategy, which combines mechano-regulated TAMs reprogramming with exosome-triggered immune responses, introducing a distinctive mechano-immunotherapeutic paradigm.

Piezo1; TAMs; in situ mechanical regulation; tumor immunomodulation; tumor mechanobiology.