Breaking physical and immunological barriers: a neutrophil-mimicking nanotherapeutics for enhanced pancreatic cancer immunotherapy

Background The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is severely limited by the highly immunosuppressive and fibrotic tumor microenvironment (TME). The aberrantly aligned extracellular matrix (ECM) forms a formidable physical barrier that impedes cytotoxic T cells infiltration while promoting immune suppression. Developing strategies capable of effectively restructuring this pathological stromal architecture to augment immune rejection and mitigate the immunosuppressive TME, thereby enhancing the efficacy of immunotherapy, remains critical. Methods A biomimetic nanomedicine (NM-PL@DDR1) was developed by encapsulating DDR1 and LOXL2 inhibitors within amphiphilic peptide micelles and coating them with neutrophil membranes. We characterized the nanoparticle's physicochemical attributes and immunomodulatory functions in vitro . Using orthotopic PDAC mouse models, we investigated the in vivo targeting ability, ECM remodeling efficacy, and antitumor immunity. The study further assessed the combinatorial therapeutic potential of NM-PL@DDR1 with PD-1 blockade. Results The successfully constructed NM-PL@DDR1 exhibited favorable physiochemical characteristics, excellent stability, and a pH-responsive drug release profile. Coating with a neutrophil membrane conferred superior tumor-targeting ability and inflammatory tropism, facilitating high accumulation at the tumor site. In vivo , NM-PL@DDR1 effectively remodeled the linearized collagen architecture into a disorganized state without reducing the collagen content, thereby disrupting the physical barrier. This remodeling was accompanied by a significant increase in the infiltration of T cells and M1 macrophages. Consequently, compared with anti-PD-1 monotherapy, the combination of NM-PL@DDR1 with an anti-PD-1 antibody demonstrated superior antitumor efficacy, achieving a 52% reduction in tumor weight, which was associated with the enhanced cytotoxic function of CD8⁺ T cells. Conclusions This study demonstrates NM-PL@DDR1 as an innovative biomimetic nanoplatform that can simultaneously normalize aberrant matrix architectural arrangement and reprogram the immunosuppressive TME. Our findings provide evidence that restructuring the stromal architecture constitutes a promising strategy for enhancing the efficacy of checkpoint blockade immunotherapy in patients with PDAC. This preclinical study offers a promising combinatorial strategy that warrants further evaluation for overcoming the immunotherapeutic resistance characteristic of this highly lethal malignancy.