## 3 Results
### Immunotherapy
#### 3.5.2 Nanoparticles Carrying Checkpoint Inhibitors  
Checkpoint inhibitors, such as those targeting PD-1/PD-L1, have revolutionized cancer immunotherapy by reactivating anti-tumor T-cell responses. However, their efficacy in HCC has been limited due to the immunosuppressive tumor microenvironment. Nanoparticle-based delivery systems are being developed to improve the delivery and efficacy of these inhibitors in HCC [87].  
In their work, [PERSON] et al. introduced a dual-functional nanobubble platform incorporating both a PD-L1 antibody and the sonosensitizer Chlorin E6 (Ce6) for the treatment of hepatocellular carcinoma. By integrating immune checkpoint blockade with ultrasound-triggered sonodynamic therapy (SDT), this approach aimed to enhance tumor-specific cytotoxicity and immune activation. The PD-L1 Ab/Ce6-NBs increased ROS production upon ultrasound exposure, leading to immunogenic cell death and the release of tumor-associated antigens. This, in turn, activated natural killer cells and CD8\({}^{+}\) cytotoxic T lymphocytes, alongside elevated expression of immune-stimulatory markers such as calcreticulin (CRT), interferon-\(\gamma\) (IFN-\(\gamma\)), interleukin-2 (IL-2), CD80, and CD86. Pro-apoptotic signaling was also reinforced. Importantly, enhanced CD8\({}^{+}\) T cell tumor infiltration and suppression of PD-L1 expression were observed, underscoring the synergistic potential of combining SDT with immune checkpoint inhibition for improved anti-HCC efficacy.  
Despite the promising results, the study has several limitations: systemic toxicity and biodistribution were not extensively evaluated, leaving potential off-target effects uncharacterized; the therapeutic efficacy was not compared with standard-of-care treatments; and the long-term immunological memory or relapse prevention remains unexplored [88].  
In a recent study, [PERSON] et al. developed a nanoplatform that combines targeted therapy with immunotherapy for treating hepatocellular carcinoma. Their approach involved hollow mesoporous silica nanoparticles loaded with sorafenib and coated with platelet membranes. These biomimetic particles were further functionalized with anti-PD-1 antibodies. The coated nanoparticles showed superior uptake in liver cancer cells and demonstrated strong stability in biological environments. In vivo experiments confirmed that this system not only improved the delivery and efficacy of sorafenib, but also promoted robust infiltration of CD8+ and CD4+ T cells into the tumor microenvironment. This immune stimulation was accompanied by reduced expression of VEGF-A and Treg cells, indicating an enhanced anti-tumor immune response. Importantly, the combination of aPD-1 and sorafenib in a single delivery system led to a more significant suppression of tumor growth than either treatment alone. The study highlights the potential of platelet-mimicking nanocarriers to simultaneously target tumor cells and modulate immune responses, paving the way for more effective and personalized therapeutic strategies in HCC. Despite its innovative approach, the study presents several important limitations. Long-term safety, including the assessment of immune-related adverse effects, was not evaluated. Moreover, the platelet-based nanoparticle system may encounter scalability and translational challenges due to the complexity of its preparation [87].