Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, No 174 Shazheng Road, Chongqing 400044, China.
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, No 174 Shazheng Road, Chongqing 400044, China.
Acta Biomater. 2024 Oct 1;187:381-395. doi: 10.1016/j.actbio.2024.08.021. Epub 2024 Aug 28.
Although immunogenic cell death (ICD) induced by lysosomal membrane permeabilization (LMP) evidently enhance the effectiveness of antitumor immunity for triple-negative breast cancer (TNBC) with poor immunogenicity, their potential is increasingly restricted by the development of other death pathways and the repair of lysosomes by endoplasmic reticulum (ER) during LMP induction. Herein, a polydopamine nanocomposite with i-motif DNA modified and BNN6 loaded is prepared toward boosting LMP and immunotherapy of TNBC by synergy of spatially confined photoacoustic (PA) effects and nitric oxide. Combining the high-frequency pulsed laser (4000 kHz) with the intra-lysosomal assembly of nanocomposites produced spatially confined and significantly boosted PA effects (4.8-fold higher than the individually dispersed particles extracellular), suppressing damage to other cellular components and selectively reducing lysosomal integrity to 19.2 %. Simultaneously, the releasing of nitric oxide inhibited the repair of lysosomes by ER stress, causing exacerbated LMP. Consequently, efficient immune activation was achieved, including the abundant releasing of CRT/HMGB1 (5.93-6.8-fold), the increasing maturation of dendritic cells (3.41-fold), and the fostered recruitment of CD4/CD8T cells (3.99-3.78-fold) in vivo. The study paves a new avenue for the rational design and synergy of confined energy conversion and responsive nanostructures to achieve the treatment of low immunogenicity tumors. STATEMENT OF SIGNIFICANCE: A strategy of boosting lysosomal membrane permeabilization (LMP) and concomitantly preventing the repair was developed to address the immunotherapy challenge of triple-negative breast cancer. Spatially confined and significantly enhanced photoacoustic (PA) effects were achieved through DNA-guided pH-responsive assembly of polydopamine nanocomposites in lysosomes and application of a high-frequency pulsed laser. Efficient immunogenic cell death was guaranteed by selective and powerful damage of lysosomal membranes through the significant contrast of PA intensities for dispersed/assembled particles and nitric oxide release induced endoplasmic reticulum stress. The study paves a new avenue for the rational design and synergy of confined energy conversion and responsive nanostructures to achieve the treatment of low immunogenicity tumors.
尽管溶酶体膜通透性（LMP）诱导的免疫原性细胞死亡（ICD）明显增强了三重阴性乳腺癌（TNBC）的抗肿瘤免疫效果，但由于其他死亡途径的发展以及 LMP 诱导过程中内质网（ER）对溶酶体的修复，其潜力受到了越来越多的限制。在此，制备了一种具有 i-motif DNA 修饰和 BNN6 负载的聚多巴胺纳米复合材料，通过空间受限的光声（PA）效应和一氧化氮的协同作用，促进 LMP 并进行 TNBC 的免疫治疗。将高频脉冲激光（4000 kHz）与纳米复合材料的细胞内组装相结合，产生了空间受限且显著增强的 PA 效应（比单独分散的颗粒在细胞外高出 4.8 倍），抑制了对其他细胞成分的损伤，并选择性地将溶酶体完整性降低至 19.2%。同时，一氧化氮的释放抑制了 ER 应激引起的溶酶体修复，导致 LMP 加剧。因此，实现了有效的免疫激活，包括 CRT/HMGB1 的大量释放（增加 5.93-6.8 倍）、树突状细胞的成熟增加（增加 3.41 倍）以及体内 CD4/CD8T 细胞的募集增加（增加 3.99-3.78 倍）。该研究为受限能量转换和响应性纳米结构的合理设计和协同作用开辟了一条新途径，以实现低免疫原性肿瘤的治疗。
