Nanotherapeutic Heterogeneity: Sources, Effects, and Solutions.

Nanomaterials have revolutionized medicine by enabling control over drugs' pharmacokinetics, biodistribution, and biocompatibility. However, most nanotherapeutic batches are highly heterogeneous, meaning they comprise nanoparticles that vary in size, shape, charge, composition, and ligand functionalization. Similarly, individual nanotherapeutics often have heterogeneously distributed components, ligands, and charges. This review discusses nanotherapeutic heterogeneity's sources and effects on experimental readouts and therapeutic efficacy. Among other topics, it demonstrates that heterogeneity exists in nearly all nanotherapeutic types, examines how nanotherapeutic heterogeneity arises, and discusses how heterogeneity impacts nanomaterials' in vitro and in vivo behavior. How nanotherapeutic heterogeneity skews experimental readouts and complicates their optimization and clinical translation is also shown. Lastly, strategies for limiting nanotherapeutic heterogeneity are reviewed and recommendations for developing more reproducible and effective nanotherapeutics provided.

• Publication year

  2023

• Venue

  Small

• Publication date

  2023-12-05

• Fields of study

  Medicine, Materials Science

• Identifiers
  DOI 10.1002/smll.202307502PMID 38050951PMCID PMC11045328
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Revealing Population Heterogeneity in Vesicle-Based Nanomedicines Using Automated, Single Particle Raman Analysis

  2023cited by this paper
• Corrigendum to ‘Characterization of lipid-based nanomedicines at the single-particle level’ [Fundamental Research 3 (2023) 488–504]

  2023cited by this paper
• Mapping Antibody Domain Exposure on Nanoparticle Surfaces Using DNA-PAINT

  2023cited by this paper
• Anti‐cooperative Self‐Assembly with Maintained Emission Regulated by Conformational and Steric Effects

  2022cited by this paper
• Payload distribution and capacity of mRNA lipid nanoparticles

  2022cited by this paper
• Chirality at nanoscale for bioscience

  2022cited by this paper
• Mapping the relationship between total and functional antibodies conjugated to nanoparticles with spectrally-resolved direct stochastic optical reconstruction microscopy (SR-dSTORM)

  2022cited by this paper
• Clinical translational barriers against nanoparticle-based imaging agents.

  2022cited by this paper
• Ultrabright Föster Resonance Energy Transfer Nanovesicles: The Role of Dye Diffusion

  2022cited by this paper
• The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case

  2022cited by this paper
• De novo engineering of both an omega-3 fatty acid-derived nanocarrier host and a prodrug guest to potentiate drug efficacy against colorectal malignancies.

  2022cited by this paper
• Structural Characterization Study of a Lipid Nanocapsule Formulation Intended for Drug Delivery Applications Using Small-Angle Scattering Techniques

  2022cited by this paper
• Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation.

  2022cited by this paper
• Reversible conjugation of biomembrane vesicles with magnetic nanoparticles using a self-assembled nanogel interface: single particle analysis using imaging flow cytometry

  2022cited by this paper
• Quantification of Available Ligand Density on the Surface of Targeted Liposomal Nanomedicines at the Single-Particle Level.

  2022cited by this paper
• A Single-Molecule View at Nanoparticle Targeting Selectivity: Correlating Ligand Functionality and Cell Receptor Density

  2022cited by this paper
• Quantifying the heterogeneity of enzymatic dePEGyaltion of liposomal nanocarrier systems.

  2022cited by this paper
• Multicolor Super-Resolution Microscopy of Protein Corona on Single Nanoparticles

  2022cited by this paper
• Chemically induced protein cage assembly with programmable opening and cargo release

  2022cited by this paper
• Microfluidic vortex focusing for high throughput synthesis of size-tunable liposomes

  2022cited by this paper
• Ultrasound assisted chitosan coated iron oxide nanoparticles: Influence of ultrasonic irradiation on the crystallinity, stability, toxicity and magnetization of the functionalized nanoparticles

  2022cited by this paper
• 3D Printing of Dapagliflozin Containing Self-Nanoemulsifying Tablets: Formulation Design and In Vitro Characterization

  2021cited by this paper
• Correlating Super-Resolution Microscopy and Transmission Electron Microscopy Reveals Multiparametric Heterogeneity in Nanoparticles

  2021cited by this paper
• Application of Quality by Design to the robust preparation of a liposomal GLA formulation by DELOS-susp method

  2021cited by this paper
• Properties and applications of precision oligomer materials; where organic and polymer chemistry join forces

  2021cited by this paper
• A review of NMR analysis in polysaccharide structure and conformation: Progress, challenge and perspective.

  2021cited by this paper
• Gold nanoparticles synergize with bacterial lipopolysaccharide to enhance class A scavenger receptor dependent particle uptake in neutrophils and augment neutrophil extracellular traps formation.

  2021cited by this paper
• Embracing nanomaterials' interactions with the innate immune system.

  2021cited by this paper
• Lipid nanoparticles for mRNA delivery

  2021cited by this paper
• One-Pot Synthesis of Ultrasmooth, Precisely Shaped Gold Nanospheres via Surface Self-Polishing Etching and Regrowth

  2021cited by this paper
• Scalable mRNA and siRNA Lipid Nanoparticle Production Using a Parallelized Microfluidic Device.

  2021cited by this paper
• A modular approach toward producing nanotherapeutics targeting the innate immune system

  2021cited by this paper
• Comparing microfluidics and ultrasonication as formulation methods for developing hempseed oil nanoemulsions for oral delivery applications

  2021cited by this paper
• Tuning the efficacy of esterase-activatable prodrug nanoparticles for the treatment of colorectal malignancies.

  2021cited by this paper
• Propagation-Instigated Self-Limiting Polymerization of Multiarmed Amphiphiles into Finite Supramolecular Polymers.

  2021cited by this paper
• Understanding the relationship between particle size and ultrasonic treatment during the synthesis of metal nanoparticles

  2021cited by this paper
• Monitoring the Effective Density of Airborne Nanoparticles in Real Time Using a Microfluidic Nanoparticle Analysis Chip.

  2021cited by this paper
• On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles

  2021cited by this paper
• Settling dynamics of nanoparticles in simple and biological media

  2021cited by this paper
• Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines

  2021cited by this paper
• Enabling online determination of the size-dependent RNA content of lipid nanoparticle-based RNA formulations

  2021cited by this paper
• Bulk and Microfluidic Synthesis of Stealth and Cationic Liposomes for Gene Delivery Applications.

  2021cited by this paper
• Influence of the Polymer Microstructure over the Phase Separation of Thermo-Responsive Nanoparticles

  2021cited by this paper
• Quantitative Cryo-TEM Reveals New Structural Details of Doxil-Like PEGylated Liposomal Doxorubicin Formulation

  2021cited by this paper
• DNA origami

  2021cited by this paper
• A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems

  2021cited by this paper
• Active cargo loading into extracellular vesicles: Highlights the heterogeneous encapsulation behaviour

  2021cited by this paper
• Microfluidics Technology for the Design and Formulation of Nanomedicines

  2021cited by this paper
• Simultaneous, Single-Particle Measurements of Size and Loading Give Insights into the Structure of Drug-Delivery Nanoparticles.

  2021cited by this paper
• Protein nanoparticles in drug delivery: animal protein, plant proteins and protein cages, albumin nanoparticles

  2021cited by this paper
• A brain tumor-homing tetra-peptide delivers a nano-therapeutic for more effective treatment of a mouse model of glioblastoma.

  2020cited by this paper
• Reproducibility in Nanocrystal Synthesis? Watch Out for Impurities!

  2020cited by this paper
• Polyvinylpyrrolidone (PVP) impurities drastically impact the outcome of nanoparticle syntheses.

  2020cited by this paper
• A Systematic comparison of in vitro cell uptake and in vivo biodistribution for three classes of gold nanoparticles with saturated PEG coatings

  2020cited by this paper
• Nanoparticle elasticity regulates phagocytosis and cancer cell uptake

  2020cited by this paper
• A comparison of centrifugation and tangential flow filtration for nanoparticle purification: A case study on acetalated dextran nanoparticles

  2020cited by this paper
• Particle Size Distribution of Bimodal Silica Nanoparticles: A Comparison of Different Measurement Techniques

  2020cited by this paper
• Long-term effects of impurities on the particle size and optical emission of carbon dots

  2020cited by this paper
• Engineering the Orientation, Density and Flexibility of Single Domain Antibodies on Nanoparticles to Improve Cell Targeting.

  2020cited by this paper
• Dissecting Particle Uptake Heterogeneity in a Cell Population Using Bayesian Analysis.

  2020cited by this paper
• Microfluidic synthesis of polystyrene nanoparticles

  2020cited by this paper
• ‘Beneficial impurities’ in colloidal synthesis of surfactant coated inorganic nanoparticles

  2020cited by this paper
• Combined morpho-chemical profiling of individual extracellular vesicles and functional nanoparticles without labels.

  2020cited by this paper
• Engineering precision nanoparticles for drug delivery

  2020cited by this paper
• Kinetic and Thermodynamic Hysteresis in Clustering of Gold Nanoparticles: Implications for Nanotransducers and Information Storage in Dynamic Systems

  2020cited by this paper
• Transition metal impurities in carbon-based materials: Pitfalls, artifacts and deleterious effects

  2020cited by this paper
• Optimising PLGA-PEG Nanoparticle Size and Distribution for Enhanced Drug Targeting to the Inflamed Intestinal Barrier

  2020cited by this paper
• Compositional inhomogeneity of drug delivery liposomes quantified at the single liposome level.

  2020cited by this paper
• Independent Size and Fluorescence Emission Determination of Individual Biological Nanoparticles Reveals that Lipophilic Dye Incorporation Does Not Scale with Particle Size.

  2020cited by this paper
• A quantitative view on multivalent nanomedicine targeting.

  2020cited by this paper
• Site-specific bioconjugation approaches for enhanced delivery of protein therapeutics and protein drug carriers.

  2020cited by this paper
• Transient dormant monomer states for supramolecular polymers with low dispersity

  2020cited by this paper
• 3D-Printing of Structure-Controlled Antigen Nanoparticles for Vaccine Delivery

  2020cited by this paper
• Nuclear imaging approaches facilitating nanomedicine translation.

  2020cited by this paper
• Rationally Designed DNA Nanostructures for Drug Delivery

  2020cited by this paper
• Effect of endothelial cell heterogeneity on nanoparticle uptake.

  2020cited by this paper
• Transforming a toxic drug into an efficacious nanomedicine using a lipoprodrug strategy for the treatment of patient-derived melanoma xenografts.

  2020cited by this paper
• Influence of probe-sonication process on drug entrapment efficiency of liposomes loaded with a hydrophobic drug

  2019cited by this paper
• Tailoring polymer dispersity and shape of molecular weight distributions: methods and applications

  2019cited by this paper
• On the effect of ligand shell heterogeneity on nanoparticle/protein binding thermodynamics.

  2019cited by this paper
• The role of apolipoprotein- and vitronectin-enriched protein corona on lipid nanoparticles for in vivo targeted delivery and transfection of oligonucleotides in murine tumor models.

  2019cited by this paper
• Corona Composition Can Affect the Mechanisms Cells Use to Internalize Nanoparticles

  2019cited by this paper
• Molecular Mass Affects the Phase Separation of Aqueous PEG–Polycation Block Copolymer

  2019cited by this paper
• Nanoparticles in the clinic: An update

  2019cited by this paper
• Inside out: optimization of lipid nanoparticle formulations for exterior complexation and in vivo delivery of saRNA

  2019cited by this paper
• Super-resolution Microscopy for Nanomedicine Research

  2019cited by this paper
• Nanoparticle administration method in cell culture alters particle-cell interaction

  2019cited by this paper
• The origin of heterogeneous nanoparticle uptake by cells

  2019cited by this paper
• HPLC methods for purity evaluation of man-made single-stranded RNAs

  2019cited by this paper
• What Does Nanoparticle Stability Mean?

  2019cited by this paper
• Nanoemulsions and Their Potential Applications in Food Industry

  2019cited by this paper
• Role of Liposome Size, Surface Charge, and PEGylation on Rheumatoid Arthritis Targeting Therapy.

  2019cited by this paper
• Pointing in the Right Direction: Controlling the Orientation of Proteins on Nanoparticles Improves Targeting Efficiency.

  2019cited by this paper
• Dynamics of liposomes in the fluid phase

  2019cited by this paper
• Multifunctional phototheranostic nanomedicine for cancer imaging and treatment

  2019cited by this paper
• New tools for recombinant protein production in Escherichia coli: A 5‐year update

  2019cited by this paper
• Reconfigurable DNA Origami Nanocapsule for pH-Controlled Encapsulation and Display of Cargo

  2019cited by this paper
• A stochastic view on surface inhomogeneity of nanoparticles

  2019cited by this paper
• Microfluidic manufacturing improves polydispersity of multicomponent polymeric nanoparticles

  2019cited by this paper
• Nanoparticle heterogeneity: an emerging structural parameter influencing particle fate in biological media?

  2019cited by this paper

• Aggregation Tendency, Cellular Uptake, and Viability Effects of Structurally Distinct Carbazole–Phthalocyanine Gold Nanoconjugates

  2026cites this paper
• Metal nanoparticle-mediated photothermal therapy for bacterial eradication: Mechanisms, strategies, and clinical challenges.

  2026cites this paper
• Virus-like particles based on plant viruses and bacteriophages: emerging strategies for the delivery of nucleic acid therapeutics

  2026cites this paper
• Multi-dimensional analysis of single particles with sequential dual-nanopipette sensors

  2025cites this paper
• Unraveling the Heterogeneity of Cargo Distribution in the Exogenous Association of Proteins With Extracellular Vesicles.

  2025cites this paper
• Multifunctional nanoparticles in abdominal aortic aneurysm management: from basic research to clinical transformation

  2025cites this paper
• Targeting and tracking mRNA lipid nanoparticles at the particle, transcript and protein level

  2025cites this paper
• Advances in Targeted Engineered Nanoparticle-Based Therapeutics for Respiratory Diseases: Current Insights and Future Perspectives

  2025cites this paper
• Progress in the Application of Nanomaterials in Tumor Treatment

  2025cites this paper
• DNA Nanostructures for Rational Regulation of Cellular Organelles

  2025cites this paper
• Comparisons between partial and total sialoadenectomy for benign submandibular gland tumors: A systematic review and meta-analysis.

  2025cites this paper
• Radiolabeling lipoproteins to study and manage disease

  2025cites this paper
• The Nanocarrier LandscapeEvaluating Key Drug Delivery Vehicles and Their Capabilities: A Translational Perspective

  2025cites this paper
• Validated analytical approach for discriminatory in-vitro drug release assessment in ophthalmic suspension of tobramycin and dexamethasone

  2025cites this paper
• Engineered Nanoparticles for Theranostic Applications in Kidney Repair

  2024cites this paper
• Biologics, theranostics, and personalized medicine in drug delivery systems.

  2024cites this paper
• Risk factors for life-threatening complications of head and neck space infections:A systematic review and meta-analysis.

  2024cites this paper
• Single-Particle Spectroscopic Chromatography Reveals Heterogeneous RNA Loading and Size Correlations in Lipid Nanoparticles

  2024cites this paper
• Microenvironment-responsive metal-phenolic network release platform with ROS scavenging, anti-pyroptosis, and ECM regeneration for intervertebral disc degeneration

  2024cites this paper