Human Leukocyte Antigen (HLA) at the Root of Persistent Antigens and Long COVID
Here we offer a perspective on recent findings of persistent SARS-CoV-2 antigens in Long COVID1 through the lens of immunogenetic risk and protection, namely in the context of the fundamental role of Human Leukocyte Antigen (HLA) in eliminating viral infections. Specifically, we attribute the persistence of viral antigens to the lack or weak protection conferred by HLA against SARS-CoV-2 in individuals carrying HLA alleles with low binding affinities to the virus. We suggest that determining the HLA Class I and II makeup of Long COVID patients will provide valuable new information in elucidating the cause for antigen persistence underlying the development of Long COVID and pave the way for successful interventions.
DOI: 10.29245/2578-3009/2025/1.1257 View / Download PdfAdvancing Brain Tumor Immunotherapy: The Role of Nanomedicine in Primary and Metastatic Brain Tumor
The present mini-review explore the therapeutic potential of nanomedicine in advancing immunotherapy for primary and metastatic brain tumors, addressing existing challenges and paving the way for transformative precision therapy. Primary brain tumors including glioblastoma and metastases from other cancers like breast, lung etc., experiences limitation in treatment outcomes due to the tumor heterogeneity, immunosuppressive tumor microenvironment (TME), the blood-brain-barrier (BBB), and therapy resistance. Although, immunotherapies have shown promising benefits, however are hindered by immune escape, organ toxicities, and variable patient responses. Major unresolved challenges include insufficient therapeutic penetration across the BBB, the inability to reprogram the immunosuppressive TME, limited strategies to counteract dynamic tumor antigen escape, and systemic toxicities associated with conventional therapies. To address these challenges, multifunctional nanomedicines offer promising solutions through precise and controlled delivery, immunosuppressive TME modulation, and/or recalibration of immune system. Advanced nanomaterials including lipid/polymer-based system, dendrimers, and quantum dots, can co-deliver immunomodulators and chemotherapeutic/radiosensitizers, enhances BBB permeability, and activate favorable immune responses. Nanomedicines with multimodality such as localized hyperthermia (e.g. photothermal ablation), and immunogenic cell death stimulate immunological memory and improve therapeutic benefits. Furthermore, innovation in gene therapy (e.g. CRISPR-Cas9) and personalized cancer vaccines enhance targeted anti-tumor immune responses. Despite these groundbreaking advancements challenges persist, including nanoparticles-biological interactions (protein corona effects), stability, scalability, and regulatory hurdles. However, emerging trends such as 3D organoids, organ-on-a-chip system, patient-derived xenografts, and integration of AI/ML platforms, offer physiologically relevant platforms to optimize nanotherapy with better response predictions. Moreover, surface functionalization such as solid-lipid nanoparticles targeting programmed death–ligand 1 (PD-L1)-epidermal growth factor receptor (PD-L1/EGFR), have demonstrated success in augmenting the abscopal effect of radiotherapy. Radiotherapy enhances tumor antigen cross-presentation by inducing immunogenic cell death (ICD), leading to the release of tumor-associated antigens (TAAs). This process is accompanied by the release of damage-associated molecular patterns (DAMPs), such as calreticulin, HMGB1, and ATP. These signals recruit and activate dendritic cells (DCs), which engulf tumor antigens and process them via the major histocompatibility complex (MHC) class I, facilitating the activation of cytotoxic T lymphocytes (CTLs) against the tumor (S. Zhu et al., 2022). Nanoparticles (NPs) can improve antigen delivery by encapsulating tumor antigens and immune-modulatory agents, ensuring prolonged antigen presentation. Furthermore, radio-enhancing NPs, such as gold or hafnium oxide nanoparticles, intensify the effects of radiation by increasing DNA damage and reactive oxygen species (ROS) production, which strengthens the ICD response and improves antigen release (He et al., 2025). In order to further enhance immune activation, some NPs are also designed to modulate the tumor microenvironment by promoting pro-inflammatory signaling.
DOI: 10.29245/2578-3009/2025/1.1259 View / Download Pdf