Targeted nanotheranostics mitigates radiation-induced fibrosis to promote immune infiltration and enhance radio-chemotherapy in pancreatic ductal adenocarcinoma.
Journal
Biomaterials advances
Journal Volume
182
Start Page
214677
End Page
214677
ISSN
2772-9508
Date Issued
2026-05
Author(s)
Sabu, Arjun
Sarma, Ritwick Ranjan
Ramesan, Lakshminarayan
Lin, Yi-Hsuan
Chiu, Hsin-Cheng
Abstract
Radiotherapy and chemotherapy exhibit limited clinical efficacy in pancreatic ductal adenocarcinoma (PDAC) due to its dense stromal desmoplasia, acting as a physical barrier that hinders drug penetration and immune cell infiltration while also promoting the formation of intratumoral radiation-induced fibrosis (RIF). In the present study, topoisomerase I inhibitor SN-38-loaded mesoporous silica-coated BiO nanoparticles (S-MBO NPs) were prepared and camouflaged with PDAC/red blood cell hybrid membranes loaded with the stromal reprogramming drug all-trans retinoic acid. The nanotherapeutics referred to as (S-MBO@A-RPCM NPs) were found capable of effectively overcoming the stromal barrier, mitigating RIF, and enhancing the radio/chemotherapeutic efficacy against PDAC. Both the in vitro and in vivo studies strongly confirmed the homotypic uptake and homologous targeting ability of S-MBO@A-RPCM NPs. The combined radiosensitizing effects of BiO and SN-38 resulted in enhanced DNA damage in UN-KC-6141 cells, decreased colony formation, and induction of immunogenic cell death by combined chemo/radiotherapy. Biodistribution data of S-MBO@A-RPCM NPs showed enhanced homologous targeting property toward PDAC, attributed to the hybrid membrane coating extracted from erythrocytes and UN-KC-6141 cancer cells on NPs. Importantly, S-MBO@A-RPCM NP treatment was found capable of deactivating the activated pancreatic stellate cells induced by radiation and TGF-β-thereby directly mitigating the fibrogenic activity characteristic of RIF in vitro and in vivo. Significantly reduced expression of α-SMA, collagen I, and fibronectin was observed after the treatment, accounting largely for the disruption of the stroma barrier, chronic inflammation signaling and tumor-stroma crosstalk, resulting in enhanced sensitization of UN-KC-6141 cells to SN-38 and radiation alongside improved immune infiltration. The in vivo data strongly signify that combining radiotherapy with the treatment of S-MBO@A-RPCM NPs exhibits superior tumor microenvironment reprogramming, attenuation of RIF and effective tumor growth inhibition in UN-KC-6141 tumor-bearing mice with minimal side effects.
Subjects
Combined therapy
Hybrid cell membrane coating
Nanotheranostics
PDAC
Radiation-induced fibrosis
Type
text::journal::journal article