Following our call to join in the discussion over the suitability of implementing a reporting checklist for bio-nano papers, the community responds. Below we report short extracts highlighting the main messages of the correspondences we received. The interested readers can find the complete pieces in the accompanying Supplementary Information.

Identifying key factors that govern in vivo behaviors of nanomaterials is critical to future clinical translation of nanomedicines. Shadowed by size-, shape- and surface-chemistry effects, the impact of particle core density on clearance and tumor targeting of inorganic nanoparticles (NPs) remains largely unknown. By utilizing a class of ultrasmall metal NPs with the same size and surface chemistry but different densities as model, we found that both renal clearance and passive tumor targeting of the NPs are strongly correlated with their densities: with the decrease of particle density, renal-clearance efficiency exponentially increased in the early elimination phase but passive tumor targeting was linearly decreased. Through systematic investigation on their pharmacokinetics, biodistribution and kidney filtration, we found that lower density NPs more easily distribute in the body and have shorter retention in highly permeable organs such as kidneys than the higher ones. These density-dependent in vivo behaviors are likely due to the fact that high-density AuNPs marginated to the blood vessel walls more quickly than low-density NPs; as a result, they circulated slowly in the laminar blood flow than the low-density ones. These new findings highlight the importance of particle density in tailoring of in vivo behaviors of engineering NPs and might open up a new pathway for designing nanomedicines with desired functionalities together with other key factors.

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.

Efficient renal clearance has been observed from ultrasmall zwitterionic glutathione-coated gold nanoparticles (GS-AuNPs), which have broad preclinical applications in cancer diagnosis and kidney functional imaging. However, origin of such efficient renal clearance is still not clear. Herein, we conducted head-to-head comparison on physiological stability and renal clearance of two zwitterionic luminescent AuNPs coated with cysteine and glycine-cysteine (Cys-AuNPs and Gly-Cys-AuNPs), respectively. While both of them exhibited similar surface charges and the same core sizes, additional glycine slightly increased the hydrodynamic diameter of the AuNPs by 0.4 nm but significantly enhanced physiological stability of the AuNPs as well as altered their clearance pathways. These studies indicate that the ligand length, in addition to surface charges and size, also plays a key role in the physiological stability and renal clearance of ultrasmall zwitterionic inorganic NPs.

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics.T his requires af undamental understanding of how engineered nanoparticles impact the targeting-clearance and permeation-retention paradoxes in the anticancer-drug delivery.Herein, we systematically investigated how renal-clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues.R enal-clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability.T he renal-clearable AuNPs also accelerated body clearance of off-target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long-standing paradoxes in the anticancer drug delivery.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.