Innate Immune Invisible Ultrasmall Gold Nanoparticles—Framework for Synthesis and Evaluation

Abstract

Nanomedicine is seen as a potential central player in the delivery of personalized medicine. Biocompatibility issues of nanoparticles have largely been resolved over the past decade. Despite their tremendous progress, less than 1% of applied nanosystems can hit their intended target location, such as a solid tumor, and this remains an obstacle to their full ability and potential with a high translational value. Therefore, achieving immune-tolerable, blood-compatible, and biofriendly nanoparticles remains an unmet need. The translational success of nanoformulations from bench to bedside involves a thorough assessment of their design, compatibility beyond cytotoxicity such as immune toxicity, blood compatibility, and immune-mediated destruction/rejection/clearance profile. Here, we report a one-pot process-engineered synthesis of ultrasmall gold nanoparticles (uGNPs) suitable for better body and renal clearance delivery of their payloads. We have obtained uGNP sizes of as low as 3 nm and have engineered the synthesis to allow them to be accurately sized (almost nanometer by nanometer). The synthesized uGNPs are biocompatible and can easily be functionalized to carry drugs, peptides, antibodies, and other therapeutic molecules. We have performed in vitro cell viability assays, immunotoxicity assays, inflammatory cytokine analysis, a complement activation study, and blood coagulation studies with the uGNPs to confirm their safety. These can help to set up a long-term safety-benefit framework of experimentation to reveal whether any designed nanoparticles are immune-tolerable and can be used as payload carriers for next-generation vaccines, chemotherapeutic drugs, and theranostic agents with better body clearance ability and deep tissue penetration.

Nanomedicine: controlling nanoparticle clearance for translational success

“…NP recognition by phagocytes is mediated through protein opsonisation. This means that the formation and composition of an NP's corona greatly determines its uptake by the MPS [7]. The conventional approach to reducing phagocyte recognition involves the use of antifouling and hydrophilic polymers, such a polyethylene glycol (PEG) and zwitterionic polymers, to cloak the surface of the NPs, whereas true bioinvisibility requires the presence Glossary α-phase half-life: the time it takes for the plasmon concentration of a drug to drop by half due to the rapid redistribution from the central to the peripheral compartments.…”

In Vivo Behavior of Ultrasmall Spherical Nucleic Acids

“…[27][28][29][30] Conversely, nanoparticles that are smaller than 10 nm ("ultrasmall" nanoparticles) exhibit different behavior from larger nanoparticles. [31] Ultrasmall nanoparticles are cleared through the kidneys -an elimination route that is faster than the hepatic accumulation and slow metabolism of larger nanoparticles. [32][33][34]31] While this leads to lower accumulation in off-target organs (i.e., decreased off-target toxicity), it also decreases accumulation in the target organ (e.g., tumor).…”

Immune Profiling and Multiplexed Label‐Free Detection of 2D MXenes by Mass Cytometry and High‐Dimensional Imaging

“…Collectively, these results indicated that MXenes can be detected in immune cells without affecting cell functionality, unlike other nanomaterials that can boost the immune system responses, altering cell functions. [28,[40][41][42][43] The good biocompatibility of MXenes, is probably due to their favorable chemistry. In particular, Ti-, Nb-, Mo-, and Ta-based MXenes selected in this study, are all composed by biocompatible transition metals used in medical settings as metal alloy implants, contrast agents, and biomaterial surface coatings.…”