Natural killer (NK) cells, particularly cytokine-induced memory-like (CIML) NK cells, represent the immune system's vanguard against malignancy, characterized by long-term persistence and hyper-responsive antitumor cytotoxicity. However, the broad clinical translation and preventive application of CIML NK cell therapies remain severely constrained by the high costs, labor intensity, and logistical burdens associated with patient-specific leukapheresis and ex vivo cell manufacturing.
A study published in Molecular Therapy, led by Prof. LI Yang and first-authored by Dr. YUAN Feng from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS), reported an innovative strategy that turns the host lung into an in vivo bioreactor, generating functional memory-like NK cells directly inside the living body without ex vivo cell manipulation.
The platform leverages an inhalable, biodegradable amorphous nanosilica (nSiO2) system to engage an obligate alveolar macrophage (AM)–NK cell circuit within the pulmonary microenvironment. Upon inhalation, the nanoparticles are selectively engulfed by lung-resident AMs, triggering a localized, transient "triple pulse" of cytokines: IL-12, IL-15, and IL-18. As circulating NK cells continuously flow through the dense pulmonary vasculature, they receive this biochemical signal and are efficiently reprogrammed into long-lasting, memory-like effectors. Furthermore, the researchers identified the particle's specific surface area (SSA) and nanoscale irregular morphology as the decisive physical parameters governing macrophage activation potency.
Crucially, the team decoupled beneficial immunostimulation from the risk of silicosis. Unlike toxic crystalline silica, which causes progressive pulmonary fibrosis, the amorphous safely biodegrades into non-toxic orthosilicic acid () and is completely cleared from the lungs within 90 days, without inducing lung fibrosis or systemic organ toxicity.
In preclinical animal models, a brief prophylactic inhalation regimen installed durable immune protection lasting over 60 days, significantly inhibited melanoma growth, and markedly delayed post-surgical local tumor recurrence. When combined with anti-PD-1 checkpoint inhibitors, pulmonary priming synergistically unlocked the full cytolytic degranulation capacity of the programmed NK cells to eradicate tumors.
These findings break away from the conventional paradigm of "manufacturing cells ex vivo before reinfusion," providing a scalable, "off-the-shelf" platform for in situ immune programming with broad translational promise for cancer immunoprevention, post-operative adjuvant care, and combination immunotherapies.
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