Journal of Nanobiotechnology最新文献

Lung metastasis remains a determinant of poor prognosis and survival in breast cancer and is understood to depend on a permissive pulmonary immune niche rather than tumor cell traits alone. Here, we developed a host-directed RNA interference strategy to modulate this niche by reprogramming pulmonary B cells for breast cancer lung metastasis treatment. IF7C peptide-decorated cationic liposomes were constructed, which preferentially accumulated in the lung, and were internalized by pulmonary B cells, enabling selective silencing of annexin A1 (ANXA1). In tumor-conditioned primary B cells, ANXA1 knockdown reshaped the transcriptional landscape and shifted cytokine output away from an immunosuppressive profile characterized by IL-10, TGF-β, and IL-35. Functionally, ANXA1-silenced B cells lost their capacity to drive CD4⁺ T cells toward Foxp3⁺ regulatory differentiation and instead promoted Th1 features, while concurrently relieving suppression of CD8⁺ T-cell proliferation. In two postoperative syngeneic breast cancer models, perioperative administration achieved ANXA1 silencing in pulmonary B cells, reduced lung Treg accumulation, enhanced CD8⁺ T-cell infiltration and effector activity, and suppressed metastatic outgrowth with favorable systemic safety. These findings identify pulmonary B cells as an actionable regulator of the lung metastatic niche and establish perioperative, B-cell-focused ANXA1 silencing as a practical approach to prevent postoperative lung metastatic recurrence.

Background: Plectin-1 (PLEC) is a membrane-associated biomarker implicated in the progression of pancreatic ductal adenocarcinoma (PDAC) and is an attractive target for molecular imaging. However, peptide-based radiotracers targeting PLEC remain limited, and the mechanisms linking plectin-1 relocalization to aggressive biology have yet to be fully elucidated.

Methods: In the present study, we performed stepwise in silico screening to identify membrane-associated metastatic drivers in PDAC. Then, we performed convolutional neural network-assisted docking to guide the design of ⁶⁸Ga-labeled NOTA-conjugated plectin-1-targeted monomeric (FZPN) and dimeric (FZPN-dimer) radiotracers. Radiochemical characterization, surface plasmon resonance, cellular uptake, blocking, pharmacokinetic, microPET/CT, biodistribution, and preliminary toxicity studies were then undertaken in PANC-1 models. Mechanistic studies assessed the subcellular localization of PLEC, its interaction with EP300, acetylation, and the functional role of lysine 1310 (K1310).

Results: PLEC emerged as the top membrane-enriched, metastasis-linked, and prognostically adverse candidate for PDAC. Analysis demonstrated that the [⁶⁸Ga]Ga-NOTA-FZPN-dimer exhibited high affinity for PLEC, favorable hydrophilicity and stability, and significantly higher cellular uptake and tumor accumulation than the monomeric tracer, with receptor-specific blockade in vitro and in vivo. In PANC-1 xenografts, tumor uptake of the dimer reached 3.8 ± 0.5%ID/g at 30 min after injection and remained higher than that of the monomer at all imaging time points. Mechanistically, PDAC tissues exhibited membrane-enriched PLEC; EP300 interacted with PLEC, acetylation was increased in PDAC cells, and the deacetylation-mimetic PLEC-K1310R mutant redirected plectin-1 away from the plasma membrane and reduced cell migration.

Conclusions: Collectively, our findings show that [⁶⁸Ga]Ga-NOTA-FZPN-dimer represents a promising PLEC-targeted PET radiotracer for molecular imaging in PDAC. EP300-mediated acetylation at K1310 appears to drive the membrane relocalization of PLEC and promote the migration of tumor cells, providing biological support for PLEC-targeted imaging and a rationale for further translational development.