While anti-PD-L1 antibody (αPD-L1) therapy holds promise, its efficacy against lung cancer brain metastasis (LCBM) is severely limited by the blood-brain barrier (BBB), the immunosuppressive tumor microenvironment and adaptive immune resistance. To overcome these barriers, we engineered a pH-responsive nanocomposite (VP-αPD-L1@REB) by functionalizing brain-metastatic tumor cell-derived exosomes (EB) with RGD peptides (REB) for targeted co-delivery of verteporfin (VP) and αPD-L1. Benefiting from homotypic affinity and integrin-mediated transcytosis, VP-αPD-L1@REB efficiently crosses the BBB, accumulates within intracranial tumors, and undergoes pH-responsive cargo release. Mechanistically, VP induces a lethal reactive oxygen species (ROS) storm for direct tumor ablation. Simultaneously, VP downregulates the chaperone protein CMTM6 and activates cellular autophagy, forcibly driving internalized PD-L1 toward degradation via dual “endosome-lysosome” and “autophagy-lysosome” pathways. Driven by the synergy of VP's robust intracellular clearance and αPD-L1's surface blockade, this targeted nanoplatform successfully remodels the intracranial immunosuppressive microenvironment and triggers potent systemic anti-tumor immunity. This study provides a highly promising translational paradigm for overcoming adaptive immune resistance in central nervous system (CNS) malignancies.
Xiujuan Hong, Xiao-Qi Wang, Wan-Kun Wang et al.· Materials Today Bio· 0 citations
BACKGROUND
Ulcerative colitis (UC) remains a major therapeutic challenge. Although natural polysaccharides exhibit therapeutic potential, their structure-activity relationships are still unclear, which limits their clinical application.
PURPOSE
This study aimed to investigate the protective effect of a rhubarb-derived pectic polysaccharide (RP-2) against UC and elucidate its underlying mechanisms.
METHODS
The structural characteristics of RP-2 were determined by monosaccharide composition analysis, methylation analysis, and the thiobarbituric acid assay. Its distribution within the colon was observed through in vivo fluorescence imaging, and the therapeutic activity was assessed using a DSS-induced UC model. Changes in the gut microbiota caused by RP-2 were investigated through 16S rRNA sequencing together with an antibiotic depletion experiment. The possible immunomodulatory actions were also explored by ELISA, flow cytometry, western blotting, and qRT-PCR, focusing on the TLR4/MyD88/NF-κB pathway, Th17/Treg balance, and maintenance of intestinal barrier integrity.
RESULTS
Structural characterization indicated that RP-2 is a complex pectic polysaccharide containing homogalacturonan, rhamnogalacturonan-I, and rhamnogalacturonan-II domains, and it exhibited prolonged retention in the inflamed colon. In RAW264.7 macrophages, RP-2 reduced the release of pro-inflammatory cytokines and the generation of reactive oxygen species following LPS stimulation. In DSS-induced UC mice, RP-2 markedly alleviated disease severity, reducing colon shortening and improving histological scores. Furthermore, RP-2 modulated gut microbial composition by enriching beneficial SCFA-producing bacteria, restored intestinal immune homeostasis, and attenuated DSS-induced intestinal barrier disruption. Notably, antibiotic-mediated microbiota depletion largely abrogated the protective effects of RP-2, highlighting the critical role of gut microbiota in its therapeutic efficacy. Mechanistically, RP-2 suppressed activation of the TLR4/MyD88/p65 pathway and restored the Th17/Treg balance.
CONCLUSION
These findings demonstrated that RP-2 alleviates UC through the microbiota-dependent "microbiota-metabolite-immune-barrier" axis, providing a scientifically grounded, natural product-based strategy for UC treatment.
