Photoimmunotherapy (PIT) employs photosensitizers that generate reactive oxygen species (ROS) under near-infrared laser irradiation to induce immunogenic cell death (ICD) and trigger systemic antitumor immunity. However, the hypoxic conditions within tumors markedly reduce photosensitization efficiency and therapeutic efficacy. Moreover, insufficient immune activation together with the profoundly suppressive tumor immune microenvironment further compromises treatment outcomes. Given these challenges, it is imperative to develop an integrated therapeutic platform capable of effectively overcoming these limitations. Here, a responsive delivery system has been developed that utilizes ROS and incorporates the immunomodulatory agent Astragalus polysaccharide (APS). Hydrophobic rapamycin (RAPA) is linked to the APS backbone through an ROS-sensitive thioether TK bond, forming the amphiphilic APS-TK-RAPA (ATKR) conjugate. Subsequently, the photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) is integrated into the system. The designed ATKR conjugate carrier facilitates the maturation of dendritic cells (DCs), effectively captures antigens released during PDT, and enhances antigen presentation. This further amplifies the adaptive immune response mediated by the APS-based carrier, thereby strengthening antitumor efficacy. In summary, ATKR with superior biocompatibility effectively surmounts the delivery challenges of hydrophobic photosensitizers. Moreover, it offers a promising nanoscale platform to address the critical issue of hypoxia in photodynamic therapy for cancer, serving as an effective inducer for augmenting immune responses.

Existing studies have shown that probiotic fermentation can enhance the pharmacological activity of Chinese herbal medicines. Astragalus Radix (AR), a medicinal and edible herb, has rarely been reported regarding its fermentation. In this study, Lactobacillus rhamnosus GG (LGG) was used to ferment AR. By integrating sensory analysis, untargeted metabolomics, and evaluation of immune function and intestinal barrier integrity, we aimed to link fermentation-driven chemical remodeling with enhanced bioactivity. The results indicated that in fermented AR (FAR), the total flavonoid content increased by 23.5% (P < 0.05). Metabolomics analysis revealed that 208 compounds were significantly up-regulated and 485 compounds were significantly down-regulated in FAR compared with AR (P < 0.05), leading to significant differences in flavor between FAR and AR. Subsequently, we evaluated the intervention effects of AR and FAR in cyclophosphamide-induced immunosuppressed mice. AR and FAR significantly restored the immune organ indices, increased blood cell counts, and elevated immunoglobulin levels. Specifically, FAR increased WBC, PLT, and LYMPH counts by 147.48%, 55.76%, and 149.55%, and IgA, IgG, and IgM levels by 37.15%, 33.88%, and 45.96%, respectively (compared with the CTX group, P < 0.05). FAR significantly repaired the intestinal barrier, increasing the expression of ZO-1, occludin, and claudin-1 across the jejunum and colon compared to the CTX group (P < 0.05), with efficacy superior to AR. Furthermore, FAR suppressed intestinal inflammation by inhibiting the NF-κB pathway, effectively restoring the phosphorylation levels of p-P65 and p-IκBα to normal baseline values. In addtion, FAR reshaped the gut microbiota composition by increasing microbial richness and selectively enriching SCFA-producing and beneficial genera, such as unclassified Lachnospiraceae, Blautia and Muribaculum, thereby restoring the microecological balance disrupted by CTX.