Wenwen Sun,Shiyun Huang,Zhihong Sun,Qi Zhao,Jie Li,Baoyu Wen,Jie Liu,Guanjun Deng,Chengming Sun
Immune checkpoint blockade (ICB) has shown promising potential for treating triple-negative breast cancer (TNBC), but its efficacy is limited, mainly due to the “cold,” suppressive immune tumor microenvironment (TME). Therefore, improving the TME is crucial for enhancing therapeutic effects against TNBC. Here, we presented a multifunctional nanotherapeutic platform (ALEvs@LNPs) designed to combine cytokine-sensitized mild photothermal therapy, ICB, and interleukin-2 (IL2) mRNA therapy to reprogram the TME, thereby improving the efficacy of ICB therapy in TNBC. Tumor cell-derived exosome-camouflaged lipid nanoparticles with antilymphocyte activation gene-3 (LAG3) were developed to codeliver the photothermal agent IR806, IL2 mRNA, and LAG3 inhibitory antibody (anti-LAG3). Mild photothermal therapy facilitated the reprogramming of “cold” tumors into “hot,” thereby enhancing the therapeutic effects of ICB. Meanwhile, ICB also promoted cytokine secretion, increasing the sensitivity of tumor cells to heat. Additionally, IL2 mRNA therapy induced T-cell proliferation and activation, further augmenting the efficacy of ICB. Together, these three therapies established a positive feedback loop that enhanced the therapeutic effects of ICB. This multifunctional nanotherapeutic platform effectively reprogrammed the “cold,” suppressive immune TME, offering a promising strategy for TNBC treatment.
Mitochondrial dysfunction-mediated ribosomal translation suppression is a hallmark of aging and a major driver of degenerative diseases, limiting mRNA therapy efficacy. Here, ionizable coenzyme Q10 (iCoQ10)-engineered lipid/fiber microplexes (iCLNP@SF) are developed that restore the mitochondrial-ribosomal axis to enhance mRNA translation. iCoQ10 replaces conventional ionizable lipids to form prodrugged lipid nanoparticles (iCLNP), stabilized by injectable polydopamine‑modified short fibers for in situ administration. In vitro efficacy assessments showed that iCLNP@SF synergistically enhanced mitochondrial metabolism and mRNA translation in senescent cells. Further mechanistic studies revealed that iCLNP stabilized mitochondrial membrane potential, suppressed cGAS-STING activation, and reduced eIF2α phosphorylation, thereby enhancing translation. In vivo, iCLNP@SF delivery of Gas6 mRNA increased hair follicle density by ≈50% in an androgenetic alopecia mouse model, while Runx2 mRNA delivery raised new bone formation (BV/TV) to ≈40% in defect models, both markedly outperforming conventional LNPs. Together, these findings highlight a strategy that improves mRNA therapy for degenerative diseases.
危险品化学品经营许可证（带存储）