A modular approach toward producing nanotherapeutics targeting the innate immune system

Abstract

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein A1–based nanobiologics with favorable innate immune system–engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.

Regulating trained immunity with nanomedicine

“…An additional level of refinement can be achieved by a concept called modularity of functionalization, that is, designing nanoparticle platforms that allow straightforward integration of therapeutic functionalities, without compromising the platform's in vivo features. Modularity is an innate feature of RNA-based therapeutics 172 , but can also be implemented for other types of therapeutics, for example, smart pro-drug approaches for small-molecule drugs 62 . Regulatory bodies, such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), should develop an approval process for nanomedicine platforms that can be modularly functionalized with diverse therapeutic payloads.…”

“…This process can be mitigated by using bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a glutaminase inhibitor 60 . Trained immunity can also be modulated by directly targeting the TCA cycle, for example, with dimethyl malonate, which is an inhibitor of succinate oxidation 61 that can be incorporated into a nanobiologic platform 62 . By inhibiting succinate oxidation, dimethyl malonate prevents fumarate accumulation and its downstream epigenetic effects.…”

“…Water-soluble compounds can be incorporated into the aqueous interior of liposomes or polymersomes, whereas micelles and nanoemulsions can carry lipophilic molecules. For example, prodrugs can be modularly integrated into apolipoprotein A1-based nanobiologics 62 , allowing greater than 80% to 90% integration of prodrug derivatives of diethylmalonate and rapamycin. Small-molecule drugs can also be integrated into viral nanoparticles.…”

Intra-Organ Delivery of Nanotherapeutics for Organ Transplantation

“…A key advantage of intraorgan delivery of NPs is to suppress the activation of Toll-like receptors (TLRs) in the antigen presenting cells (APCs). Dendritic cells (DCs) can project cellular extensions into the lumina of blood vessels that can capture NPs from the circulation. , Thus, coating the surface of NPs with antibodies against the macrophage antigen CD11b and dendritic cell antigen CD11c may increase their uptake into organs through direct interaction with these cells. IRI results in the opening of connexin hemichannels, so a greater number of NPs may cross the endothelium between adjacent cells and undergo internalization by APCs of ischemic organs.…”

Embracing nanomaterials' interactions with the innate immune system

“…Furthermore, the broad scope of innate immune responses facilitates treating a wide variety of diseases and disorders. For example, we developed lipoprotein-based nanotherapeutics loaded with tolerance-inducing rapamycin and used these to effectively promote heart allograft survival (Van Leent et al, 2021). Similarly, we significantly reduced tumor growth using bone marrow-avid lipid nanocarriers decorated with immunogenic peptidoglycan derivatives, capable of activating the intracellular nucleotide-binding oligomerization domain-containing protein 2 (NOD2) PRR (Priem et al, 2020).…”