Natural killer (NK) cells, particularly cytokine-induced memory-like (CIML) NK cells, serve as the immune system's first line of defense against malignancy and are characterized by long-term persistence and hyperresponsive antitumor cytotoxicity. However, the broad clinical translation and preventive use of CIML NK cell therapies remain severely limited by the high costs, labor intensity, and logistical burdens of patient-specific leukapheresis and ex vivo cell manufacturing.

A new study published in Molecular Therapy, led by Prof. LI Yang and with Dr. YUAN Feng as the first author, from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS), reports a strategy that uses the host lung as an in vivo bioreactor, generating functional memory-like NK cells directly in the body without ex vivo cell manipulation.

The platform uses 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. The researchers also identified the particles' specific surface area (SSA) and nanoscale irregular morphology as the decisive physical parameters governing macrophage activation potency.

The team also investigated whether the immunostimulatory effects could be achieved without the risk of silicosis. Unlike toxic crystalline silica, which causes progressive pulmonary fibrosis, the amorphous nanosilica 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 induced 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 enhanced the cytolytic degranulation capacity of the programmed NK cells, leading to tumor eradication.

According to the researchers, the findings offer an alternative to the conventional approach of manufacturing cells ex vivo before reinfusion and provide a scalable, "off-the-shelf" platform for in situ immune programming, with potential applications in cancer immunoprevention, post-operative adjuvant care, and combination immunotherapies.