The glomerular filtration barrier is known as a “size cut-off” slit to retain nanoparticles or proteins larger than 6~8 nm in the body, and to rapidly excrete the smaller ones through the kidneys. However, in a sub-nm size regime, we found that this barrier behaved as an atomically precise “bandpass” filter to significantly slow down renal clearance of few-atom gold nanoclusters (AuNCs) with the same surface ligands but different sizes (Au18, Au15 and Au10–11). Compared to Au25 (~1.0 nm), just few-atom decreases in the size resulted in 4~9 times reductions in the renal clearance efficiency in the early elimination stage because the smaller AuNCs were more readily trapped by the glomerular glycocalyx than the larger ones. This unique in vivo nano-bio interaction in the sub-nm regime also slows down the extravasation of sub-nm AuNCs from normal blood vessels and enhances their passive targeting to cancerous tissues through enhanced permeability and retention effect. This discovery highlights the size precision in the body’s response to nanoparticles and opens a new pathway to develop nanomedicines for many diseases associated with glycocalyx dysfunction.
Gene therapy uses nucleic acids as functional molecules to activate biological treatment for a wide range of diseases, such as cancer 1,2 , cystic fibrosis 3 , heart disease 4 , diabetes 5 , haemophilia and HIV/AIDS 6 . Nucleic acids have been attracting increasing attention owing to the global effort in the human genome elucidation together with recent discoveries such as RNA interference (RNAi) and CRISPR-based genome editing [7][8][9] . Gene therapy uses genetic material to alter the expression of a target gene or to modify the biological properties of living cells for therapeutic needs. In recent years, multiple gene therapy products have been approved by the regulatory agencies for various applications 10 . Perhaps the most relevant example is the authorization of mRNA vaccines to fight the COVID-19 outbreak 11 .Gene therapy can be divided into three main avenues, as detailed in Fig. 1. First is editing mutated genes using CRISPR-Cas technology to cause gain or loss of function 12,13 . Second, upregulating gene expression can be achieved through the insertion of a functional gene copy to be expressed by using molecules such as DNA plasmid (pDNA), minicircle DNA (mcDNA), synthetic mRNA, circular RNA and self-amplifying RNA (saRNA) [14][15][16] . Last is downregulating gene expression using molecules such as small interfering RNA (siRNA), antisense oligonucleotides (ASOs), short hairpin RNA (shRNA) and microRNA (miRNA) 17,18 .Nucleic acids have promising advantages compared with conventional drugs 19 . Unlike the latter, the mechanism of action and high specificity of nucleic acids present a possible therapy route for viral infections, various cancers and undruggable genetic disorders with unmet clinical need. Moreover, theoretically, a single treatment of the genetic payload can achieve a durable and even curative effect 20 . However, delivering nucleic acids to reach their active site inside the cell is challenging owing to their low in vivo stability and rapid host clearance outside cells. Additionally, nucleic acids are poorly permeable through the cellular membrane owing to their negative charge, high molecular weight and hydrophilicity 21 . Nonetheless, few delivery challenges differ between DNA and RNA. For example, the payload and carrier toxicity are of greater concern when delivering RNA molecules usually associated with short-term activity and low retention inside the cell, hence requiring more frequent administration 22 . Alternatively, DNA activity inside the nucleus adds complexity related to low nuclear transport, thus leading to distinguishing design concepts regarding the delivery system compared with RNA molecules 23 . Together with specific challenges relevant to the delivered molecule, the fundamental challenge is to develop tailored systems that can facilitate nucleic acid uptake into target cells. The carrier itself needs to overcome extracellular and intracellular barriers, provide protection from nuclease activity in the bloodstream, enhance and assist with cellular uptake, and promote ...
Size-independent emissions have been widely observed from ultrasmall thiolated gold nanoparticles (AuNPs) but remain a mystery in fundamental understanding of photoluminescence mechanisms of noble metals on the nanoscale. Herein, we report a correlation between emission wavelengths and local binding geometries of a thiolate ligand (glutathione) on AuNPs with identical size (~2.5 nm) but two distinct emission wavelengths. Using circular dichroism, X-ray absorption and fluorescence spectroscopies, we found that high Au-S coordination number (CN)/high surface coverage resulted in strong Au(I)-ligand charge transfer, chiral conformation and 600 nm emission while low Au-S CN/low surface coverage led to weak charge transfer, achiral conformation and 810 nm emission. By fine tuning of surface coverage, these two size-independent emissions can be integrated into one single 2.5 nm AuNP, where a ratiometric pH response was observed due to strong energy transfer between two emission centers, opening up a new path to design ultrasmall ratiomteric pH nanoindicators.
Glutathione-mediated biotransformation in the liver is a well-known detoxification process to eliminate small xenobiotics but its impacts on nanoparticle retention, targeting and clearance are much less understood than liver macrophage uptake even though both processes are involved in the liver detoxification. By designing a thiol-activatable fluorescent gold nanoprobe that can bind to serum protein and be transported to the liver, we noninvasively imaged this biotransformation kinetics in vivo at high specificity and examined this process at the chemical level. Our results show that glutathione efflux from hepatocytes resulted in high local concentrations of both glutathione and cysteine in liver sinusoids, which transformed the nanoparticle surface chemistry, reduced its affinity to serum protein and significantly altered its blood retention, targeting and clearance. With this biotransformation, liver detoxification, a long-standing barrier in nanomedicine translation, can be turned into a bridge toward maximizing targeting and minimizing nanotoxicity. Liver detoxification is a natural defense response that the body uses to remove foreign materials; however, due to rapid uptake by mononuclear phagocyte system (MPS) in the liver 1, 2, 3 , it often dramatically shortens the blood retention of engineered nanoparticles, prevents them from efficiently targeting diseases and retains them in the body for a long time, which can induce long-term nanotoxicity and hamper their clinical translation, particularly for those non-degradable ones composed of toxic elements or heavy metals 4, 5. However, liver detoxification also plays an important role in minimizing toxicities of small xenobiotics. For instance, glutathione (GSH)-mediated biotransformation is one of the most common liver detoxification strategies to eliminate lipophilic molecules and heavy metals 6. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
As a bridge between individual atoms and large plasmonic nanoparticles, ultrasmall (core size <3 nm) noble metal nanoparticles (UNMNPs) have been serving as model for us to fundamentally understand many unique properties of noble metals that can only be observed at an extremely small size scale. With decades’efforts, many significant breakthroughs in the synthesis, characterization and functionalization of UNMNPs have laid down a solid foundation for their future applications in the healthcare. In this review, we aim to tightly correlate these breakthroughs with their biomedical applications and illustrate how to utilize these breakthroughs to address long-standing challenges in the clinical translation of nanomedicines. In the end, we offer our perspective on the remaining challenges and opportunities at the frontier of biomedical-related UNMNPs research.
While dose dependencies in pharmacokinetics and clearance are often observed in clinically used small molecules, very few studies have been dedicated to the understandings of potential dose-dependent in vivo transport of nanomedicines. Here we report that the pharmacokinetics and clearance of renal clearable gold nanoparticles (GS-AuNPs) are strongly dose-dependent once injection doses are above 15 mg kg : high dose expedited the renal excretion and shortened the blood retention. As a result, the no-observed-adverse-effect-level (NOAEL) of GS-AuNPs was >1000 mg kg in CD-1 mice. The efficient renal clearance and high compatibility can be translated to the non-human primates: no adverse effects were observed within 90 days after intravenous injection of 250 mg kg GS-AuNPs. These fundamental understandings of dose effect on the in vivo transport of ultrasmall AuNPs open up a pathway to maximize their biomedical potentials and minimize their toxicity in the future clinical translation.
The coming era of precision nanomedicine demands engineered nanoparticles that can be readily translated into the clinic, like that of molecular agents, without being hindered by intrinsic size heterogeneity and long-term body retention. Herein we report that conjugation of indocyanine green (ICG), an FDA-approved near-infrared (NIR) dye, onto an atomically precise glutathione-coated Au25 (GS-Au25) nanocluster led to a molecular-like photothermal nanoparticle (ICG4–GS-Au25) with significantly enhanced ICG photostability and tumor targeting. Under weak NIR light irradiation conditions, free ICG failed to suppress tumor growth but the original tumors were completely eradicated with ICG4–GS-Au25. In the meantime, “off-target” ICG4–GS-Au25 was effectively cleared out from the body like small-molecule drugs after glutathione-mediated biotransformation in the liver. These findings highlight the merits of molecular-like nanomedicines, offering a new pathway to meet FDA’s criteria for the clinical translation of nanomedicines.
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