Long-acting HIV-mimicking nanoparticles for enhanced antiretroviral delivery to lymph nodes
Embargo Date
2026-03-18
OA Version
Citation
Abstract
HIV remains a global threat despite the tremendous progress of combination antiretroviral therapy (cART). Major therapeutic challenges persist, marked by chronic inflammation increasing the risk of non-AIDS co-morbidities in people with HIV (PWH), and the emergence of HIV drug resistance, leading to treatment failure. These conditions are attributed to various factors including viral persistence in secondary lymphoid tissues such as lymph nodes (LNs). Notably, viral persistence in LNs has been linked to low and heterogeneous antiretroviral (ARV) distribution in these reservoirs. Furthermore, uptake of daily ARVs remains a burden, resulting in poor adherence and subsequent viral rebound. To address these challenges, we developed a novel approach using dual ARV-loaded long-acting membrane wrapped nanoparticles that recapitulate HIV trafficking to subcapsular sinus (SCS) CD169+ macrophages in LNs for improved ARV delivery and retention in these tissues. Previous studies have shown that monosialo di-hexosylganglioside (GM3) incorporated in the lipid membrane bilayer of HIV-1 particles binds to the lectin receptor CD169 on macrophages, thereby triggering formation of non-degradative virus-containing-compartments (VCCs) that preserve virus infectivity. Importantly, VCCs remain surface accessible and promote efficient HIV-1 trans-infection of bystander CD4+ T Cells. Consequently, in collaboration with the Reinhard lab, we designed biomimetic GM3-expressing membrane wrapped polymeric nanoparticles (GM3-PLA-NPs), that mimic HIV-1 capture and trafficking pathways by binding to CD169 and forming durable VCC-like compartments that we termed nanoparticle containing compartments (NPCCs). I hypothesized that by loading ARVs in GM3-PLA-NPs and the subsequent establishment of NPCCs in CD169+ macrophages, sustained viral inhibition can be achieved in macrophages and bystander CD4+ T cells through cell-to-cell ARV transfer. Therefore, I used GM3-PLA-NPs harboring a non-nucleoside reverse transcriptase inhibitor, Rilpivirine (RPV) and integrase inhibitor, Cabotegravir (CAB) and demonstrated that sustained preservation of GM3-PLA-NPs in CD169+ NPCCs prolonged antiviral potency against cis- and trans-infection in macrophages and CD4+ T cells, respectively, for one month.
I next sought to characterize the capacity of GM3-PLA-NPs (also referred to as GM3-NPs) to enhance ARV distribution and retention in LNs via targeting of SCS CD169+ macrophages. Subcutaneous injection of GM3-NPs in BALB/c mice displayed specific targeting to SCS CD169+ macrophages and enhanced dissemination in LNs compared to ligand-deficient (BLK) or phosphatidylserine (PS) displaying NPs. In addition, GM3-NPs persisted in CD169+ macrophages for over 35 days. Interestingly, GM3-NPs infiltrated follicular regions of LNs and were found in close proximity to CD4+ T follicular helper cells (Tfh) which are major HIV targets in the LNs.
Finally, we designed GM3-expressing lipid wrapped mesoporous silica nanoparticles (LMSNs) as an alternative to polymeric NPs, due to their enhanced stability at ambient temperatures and higher payload capacity for ARV delivery to CD169+ macrophages. I demonstrated that LMSNs extended the shelf-life of RPV and CAB and promoted antiviral synergism against HIV-1 infection. Additionally, encapsulation of mesoporous silica nanoparticles by GM3 lipid coating conferred “stealth” properties to suppress innate immune activation by encapsulated ARVs and NP cores.
These studies elucidated a new approach for safe and effective delivery of long-acting therapeutics to LNs which could be beneficial for HIV prevention and treatment. Collectively, my findings demonstrated that leveraging viral intracellular capture and trafficking routes offers a promising avenue for targeted delivery of therapeutics.
Description
2024