Leveraging self-assembled nanobiomaterials for improved cancer immunotherapy

Abstract

Nanomaterials and targeted drug delivery vehicles improve the therapeutic index of drugs and permit greater control over their pharmacokinetics, biodistribution, and bioavailability. Here, nanotechnologies applied to cancer immunotherapy are discussed with a focus on current and next generation self-assembling drug delivery systems composed of lipids and/or polymers. Topics covered include the fundamental design, suitability, and inherent properties of nanomaterials that induce anti-tumor immune responses and support anti-cancer vaccination. Established active and passive targeting strategies as well as newer "indirect" methods are presented together with insights into how nanocarrier structure and surface chemistry can be leveraged for controlled delivery to the tumor microenvironment while minimizing off-target effects.

Keywords: cancer; drug delivery; nanomaterial; targeting; tumor microenvironment; vaccine.

Figure 1.. Summary of early nanomedicine milestones, self-assembling nanocarrier classes, and principles for controlling the assembled nanocarrier structure (i.e., morphology)

(A) Early milestones for the clinical adoption of anti-cancer nanotechnologies. (B) The three major classes of self-assembling nanocarriers: liposomes, lipid nanoparticles (LNPs), and polymeric nanocarriers. (C) The critical packing parameter for self-assembling polymer amphiphiles and its influence on nanocarrier morphology. The effective hydrophobic chain volume (V), critical chain length (l_c), and effective surface area of the hydrophilic headgroup (a_h) are presented from the equation for the critical packing parameter (C_pp). The C_pp for cone and truncated cone hydrophobic tail geometries is presented in the lower panel together with the favorable morphology for the self-assembled aggregate.

Figure 2.. Overview of nanobiomaterial applications for targeted cancer immunotherapy

Major applications for targeted nanobiomaterials include anti-cancer vaccines, immune checkpoint inhibition (ICI), immunogenic cell death (ICD), and chemotherapy. Abbreviations: tumor-associated macrophages (TAMs); dendritic cells (DCs); antigen (Ag).

Figure 3.. Overview of the nanocarrier “chassis” and surface biofouling

The design of nanocarriers begins with the selection of a material type, or building block (here, polymers or lipids), which favorably self-assemble into the morphology/shape of interest. The cargo loading capability of the nanocarrier is largely determined by the chassis morphology. Potential cargoes include small molecules (traditional chemotherapeutics, photosensitizers, etc.) as well as biologics including various antigens, adjuvants, nucleic acids, etc. The ovalbumin protein (PDB ID: 1OVA) and the DNA molecule from PDB entry 4CJA are displayed for illustrative purposes. The building block should be engineered to contain terminal chemical groups of the desired atomic composition, polarity, and charge to yield the surface chemistry of interest. When designing the synthetic physicochemical properties, it is also important to understand how these design choices modulate nanocarrier interactions with biofluid proteins in a process referred to as biofouling. The formation of an adsorbed surface coating of proteins (i.e., protein corona) redefines the nanocarrier’s biochemical and cellular interactions. The identity of adsorbing protein species, their relative abundance, and the structural conformation(s) can be tuned using the physicochemical properties of the nanocarrier chassis. All surface features described here influence the pharmacokinetics, biodistribution, and inflammatory potential of the nanocarrier.

Figure 4.. Summary of common targeting strategies for directing nanocarrier interactions and payload delivery

Targeting strategies include passive and active approaches, as well as holistic approaches that combine multiple targeting strategies in a single nanocarrier formulation to maximize control over drug interactions. Abbreviations: antibody (Ab); heavy chain antibody (HCAb); antigen-binding fragment (Fab); fragment variable (Fv); single-chain variable fragment (scFv).

Figure 5.. “Indirect” targeting via macropinocytosis inhibitory nanoparticles (MiNP)

(A) Example targeted “effector” nanoparticles (E-NP) bearing cancer therapeutic cargo and displaying a folate receptor binding ligand. E-NP commonly accumulate within tumor cells at low levels due to high uptake by cells of the mononuclear phagocyte system (MPS). (B) Indirect targeting strategies provide one solution to this issue via silencing MPS uptake with micropinocytosis inhibitory nanoparticles (MiNP). The macropinocytosis inhibitor Latrunculin A (LatA) is depicted here. LatA is a 16-membered macrolide that depolymerizes actin in the cytoskeleton and blocks the incorporation of actin monomers into actin filaments (LatA-actin complex is displayed from PDB ID: 1ESV). The pre-injection of MiNP results in the safe and transient inhibition of MPS cells that are responsible for scavenging and clearing the majority of administered nanocarriers and biologics. The subsequent administration of E-NPs achieves enhanced accumulation within the TME. Aspects of this figure were adapted from Stack et al., 2021. Nanoscale Horiz. 6, 393–400.