Chapter Four · failure evidence
What Targeted Drug Delivery Systems got wrong, from 54 dissertations
Targeted drug delivery formulations and administration routes frequently encounter translational barriers spanning physiological clearance, structural vehicle instability, and physical delivery device bottlenecks. Systematic evaluations highlight that targeting efficacy depends heavily on carrier composition, encapsulation stability, and the ability to navigate biological barriers without off-target toxicity. These records come from PhD theses at 18 institutions, 2021 to 2026. Each links to its thesis. They were extracted by language models reading the full text, so treat each as a lead to read, not a verdict.
Lipid nanoparticle formulations and targeting ligands fail to achieve intended cellular uptake or organ tropism
Altering helper lipid charge, swapping full antibodies for fragment designs, or modifying surface ligands often results in inferior transfection and cellular uptake compared to established formulations. Furthermore, specific lipid compositions can misdirect payload distribution away from target sites toward clearance organs or reduce intracellular delivery potency.
Lost to a baseline
scFv-conjugated LNP formulations failed to outperform monoclonal antibody (104D2 mAb) conjugated LNPs in delivery
Lost to a baseline
Non-charge modified proteins (e.g., nanobodies, affibodies, Omomyc) failed to achieve effective intracellular delivery using the K27-optimized B6 LNP formulation compared to K27-D30.
Considered and rejected
Considered and rejected: Rejected VMAT2-mediated targeting via DTBZ in favor of GLP-1R-mediated delivery after uptake kinetics showed no advantage over GLP-1R in dispersed islet cells.
Entwicklung neuartiger gewebespezifischer Therapiekonzepte zur Behandlung von Diabetes · Leibniz Universität Hannover Repository
Considered and rejected
Considered and rejected: Decided against using poly(glutamic acid) block with 60 units (biotin-PEG2k-b-GA60) for targeted delivery because its lower surface ligand density failed to improve cellular uptake compared to GA10.
Non-covalent polymer and drug complexes as targeted delivery system for pulmonary delivery · University of Nottingham Repository
Lost to a baseline
Pfizer-BioNTech LNP underperformed Moderna LNP and IMD1/IMD2 in functional aVHH mRNA delivery across lymph node APCs.
Next-Generation Lipid Nanoparticle Formulations for Non-Liver Delivery of Nucleic Acid-Based Therapies and Vaccines · Georgia Tech
Tried and failed
post-formulation concentration of high-peg nanoparticles applied to inhalable lipid nanoparticle mrna delivery. Outcome: worse than baseline. Reason: concentrating formulations with high peg content reduced lung and alveolar cell transfection efficacy
Translational Design of Lipid Nanoparticles (LNPs) to Deliver mRNA Therapies to Solid Tumors and to the Lungs · Georgia Tech
Tried and failed
neutral or anionic lipid nanoparticle formulation applied to systemic mRNA delivery to lungs. Outcome: no signal. Reason: neutral and anionic helper lipids failed to facilitate measurable pulmonary biodistribution or transfection
Next-Generation Lipid Nanoparticle Formulations for Non-Liver Delivery of Nucleic Acid-Based Therapies and Vaccines · Georgia Tech
Tried and failed
scFv targeting moieties instead of full antibodies applied to targeted lipid nanoparticle delivery. Outcome: worse than baseline. Reason: scFv conjugated nanoparticles failed to outperform full monoclonal antibody conjugates in delivery potency
Considered and rejected
Considered and rejected: Rejected using mRNA Spleen SORT formulations (containing 18:1 PA) for pDNA delivery because they exhibited poor pDNA encapsulation (24%) and misdirected tropism to the lungs
Engineering Lipid Nanoparticle-Mediated Delivery of Nucleic Acids to Lymphoid Organs and Immune Cells · DSpace at UTSWMED
Tried and failed
incorporating cationic cholesterol in lipid nanoparticles applied to intratumoral mRNA delivery. Outcome: worse than baseline. Reason: negatively enriched compared to neutral cholesterol formulations during in vivo screening
Translational Design of Lipid Nanoparticles (LNPs) to Deliver mRNA Therapies to Solid Tumors and to the Lungs · Georgia Tech
Lost to a baseline
18:0 TAP SORT LNPs exhibited lower lung selectivity (80%) and higher off-target liver/spleen delivery compared to 18:1 TAP SORT LNPs.
Elucidating the Impact of Endogenous Proteins on Lipid Nanoparticle Organ-Targeting Outcomes · DSpace at UTSWMED
Lost to a baseline
In vitro mRNA delivery with chitosan-IAA nanoparticles showed negligible GFP transfection compared to the Lipofectamine control.
Utilizing Combinatory Adjuvant-Loaded Chitosan-Derived Nanoparticles for a Joint SARS-CoV-2/Influenza Vaccine · Georgia Tech
Systemic administration leads to rapid clearance and off-target accumulation rather than selective tissue delivery
Unencapsulated agents or rigid nanoparticles delivered systemically suffer from baseline accumulation in clearance organs and fail to enrich in target tissues such as lymph nodes or solid tumors. Local concentrations within diseased tissues often plateau due to diffusion limitations, while systemic distribution induces toxicity without providing tissue-specific benefits.
Tried and failed
increasing local drug concentration applied to intratumoral drug delivery. Reason: cell death fraction reaches an asymptotic plateau due to transport limitations and diffusion barriers
Modeling and simulation of biomedical applications using finite element method · Texas Tech
Tried and failed
small molecule drug delivery applied to in vivo tumor progression inhibition. Reason: poor bioavailability prevented advancement beyond preclinical development stages
The link between the trans-Golgi network and tumour progression · Cambridge
Tried and failed
Unconjugated small-molecule donor delivery applied to enhancing tissue nanoparticle penetration. Outcome: no signal. Reason: Free small molecule donor lacked targeted localization needed to modulate tracer uptake in vivo
Engineered biomaterials for drug delivery and therapeutic modulation in lymphatic tissues · Georgia Tech
Tried and failed
nanoparticle conjugation for targeted delivery applied to therapeutic antibodies for immune checkpoint blockade. Outcome: no signal. Reason: conjugation did not increase or alter local retention or draining lymph node accumulation versus free antibody
Analysis of Nanomaterial Physiochemical Property Influences on Lymph Node Accumulation and Leukocyte Association · Georgia Tech
Tried and failed
intravenous administration of rigid polymer nanoparticles applied to lymph node targeting and accumulation. Outcome: no signal. Reason: particles exhibited baseline-level accumulation and lacked preferential delivery over systemic clearance organs
Analysis of Nanomaterial Physiochemical Property Influences on Lymph Node Accumulation and Leukocyte Association · Georgia Tech
Considered and rejected
Considered and rejected: Liposome and systemic delivery of PRR/STING agonists were rejected due to off-target hepatic/renal clearance and systemic inflammatory toxicity
Cellular Localization Of Inflammatory Signaling As A Determinant Of Tumor-Immune Biology · Penn
Tried and failed
intravenous delivery of large PEGylated nanoparticles applied to targeted delivery to lung tissue. Outcome: worse than baseline. Reason: intravenous administration resulted in substantially lower pulmonary biodistribution compared to local intrapulmonary administration
Tried and failed
centroid-targeted drug injection for local delivery applied to solid tumor drug delivery simulation. Outcome: worse than baseline. Reason: anisotropic diffusion patterns caused non-central injection sites to achieve higher overall drug efficacy and apoptosis
Modeling and simulation of biomedical applications using finite element method · Texas Tech
Tried and failed
systemic unencapsulated small molecule drug delivery applied to lymphatic vessel function stimulation. Reason: lack of tissue specificity caused severe off-target toxicity and failed to improve local vessel pumping
Engineered biomaterials for drug delivery and therapeutic modulation in lymphatic tissues · Georgia Tech
Tried and failed
water-in-oil emulsion delivery applied to peptide antigen lymph node targeting. Outcome: worse than baseline. Reason: did not enhance lymphatic drainage or lymph node accumulation compared to free peptides
Protein Engineering for Personalized therapy and diagnosis · EPFL
Physical clogging, poor aerosolization, and excessive mechanical force disrupt device-mediated delivery
Nebulization and spray-drying methods encounter severe mechanical limitations, including membrane pore clogging, excessive particle sizes, and insufficient fine particle fractions for deep lung delivery. In addition, aggressive injection pressures and low-viscosity carrier fluids lead to vehicle sedimentation, tissue stripping, and mechanical airway obstruction.
Tried and failed
gas-pressurized jet injection of nanoparticles applied to mucosal tissue delivery. Reason: excessive delivery pressure caused gas backflow that stripped mucus and blew nanoparticles away from target tissue
High Velocity Delivery of Biologics from Self-Pressurized Oral Capsules to the Gastrointestinal Tract · Georgia Tech
Tried and failed
vibrating mesh nebulization of concentrated lipid nanoparticles applied to pulmonary nucleic acid delivery. Reason: concentrated nanoparticle formulation clogged the vibrating mesh pores and abolished in vivo expression
Development of non-viral systems for pulmonary nucleic acid delivery and gene editing · UT Austin
Tried and failed
spray drying with large nozzle diameter applied to inhalable microparticle formulation. Reason: produced particle sizes greater than 10 µm, unsuitable for deep lung delivery
Tried and failed
suspending microparticles in pure low-viscosity vehicle applied to syringe delivery of microparticle suspensions. Reason: insufficient viscous drag force caused rapid particle sedimentation and complete loss of injectability
Microscale polymeric-based technologies for controlled vaccine delivery · MIT
Lost to a baseline
Medium VMN delivered a lower proportion of dose to the lung (25.4%) compared to intranasal MAD delivery (51.9%).
Respiratory immunisation and mucosal immunity against influenza · Oxford
Considered and rejected
Considered and rejected: Ultrasonic spray freeze-drying rejected in favour of pneumatic spray freeze-drying due to limitations in achieving sufficient fine particle fraction for pulmonary delivery.
Particle Engineering via Spray Freeze-Drying for Pulmonary Drug Delivery Applications · IRIS - POLITO - prod
Considered and rejected
Considered and rejected: Rejected aerosol nebulizer delivery for antibody pulmonary bioavailability in favor of nasal drip because aerosolization achieved negligible lung concentration (0.026 vs 7.66 µg/mL) and required far more protein.
Contributions of antibodies binding defined epitopes to protection against B. pertussis and SARS-CoV-2 · UT Austin
Considered and rejected
Considered and rejected: Rejected inkjet printing (IJP) for biomacromolecule delivery devices due to persistent nozzle clogging from protein adsorption and salt precipitation.
Implementing 3D Printing for the Long-Term Release of Biomacromolecules · University of Nottingham Repository
Considered and rejected
Considered and rejected: Embedding bacteria in artificial biofilm beads (agar/agarose/alginate) deposited via tracheal incision was rejected in favor of free intranasal bacterial delivery to avoid bronchial blockages and mechanical lung damage
Carrier coating degradation, burst release, and membrane permeability cause premature payload leakage
Nanocarriers and functional coatings frequently break down in physiological environments, leading to rapid gastric dissolution, excessive burst release, and loss of sustained gene knockdown. Nanoparticle encapsulation procedures can also compromise membrane integrity, causing carrier leakage and rapid clearance by the reticuloendothelial system.
Tried and failed
surface modification for sustained drug release applied to mesoporous biomaterial vaccine delivery systems. Outcome: did not generalise. Reason: in vitro release kinetics failed to predict in vivo rapid clearance indistinguishable from unmodified controls
Developing strategies to enhance immune responses induced by mesoporous silica rod vaccines · Harvard
Tried and failed
layer-by-layer polymer coating for sustained oligonucleotide delivery applied to in vivo target gene knockdown in wounds. Outcome: unstable. Reason: Transient initial knockdown was lost over extended timepoints due to inadequate sustained release or rapid target recovery
Tried and failed
chitosan coating for acid-resistant encapsulation applied to liposomal oral drug delivery. Outcome: unstable. Reason: rapid dissolution of chitosan coating in acidic gastric medium compromised payload retention
Lost to a baseline
PAA NPs loaded with Dox via encapsulation failed to deliver Dox in vitro due to rapid burst release compared to PEI-functionalized NPs
Hierarchical Assemblies of Soft Matters From Polymers and Liquid Crystals on Structured Surfaces · Penn
Tried and failed
layer-by-layer assembly under mild ionic strength applied to nanoparticle coating for drug delivery. Outcome: worse than baseline. Reason: increased layer thickness hindered payload bioavailability and reduced therapeutic efficacy
Tried and failed
nanoparticle formulation via microfluidic mixing applied to in vivo targeted mRNA delivery. Outcome: did not generalise. Reason: re-testing and scale-up drastically reduced encapsulation efficiency and shifted organ biodistribution from target to clearance organs
Design and Formulation Optimization of Lipid Nanoparticles Carrying MRNA to the Heart and the Pancreas · Georgia Tech
Considered and rejected
Considered and rejected: Rejected using dendrimersomes as nanocarriers for small hydrophilic drug retention due to inherent membrane semipermeability to small molecules (<600 Da).
Self-assembled vesicular nanostructures for bacterial applications · Imperial
Considered and rejected
Considered and rejected: Rejected the use of erythrocyte ghosts as targeted drug delivery devices due to difficulty in loading cytotoxic compounds without causing membrane damage that triggers RES clearance, and doubts regarding tumour extravasation.
MACROPHAGE MEDIATED DRUG DELIVERY TO TUMOUR CELLS IN VITRO · De Montfort Open Research Archive (DORA)
Tried and failed
direct liposomal encapsulation without charge complexation applied to pore-forming antimicrobial peptides. Reason: failed to prevent membrane lytic activity and leakage prior to intended release
Activity-based molecular circuits for programmable medicine · Georgia Tech
Unmodified or unencapsulated therapeutics undergo rapid clearance and lack tissue retention
Formulations lacking biomaterial encapsulation, protective surface coatings, or membrane-anchoring tags fail to maintain sustained local presence at mucosal or joint injection sites. This rapid washout prevents continuous immune or paracrine signaling and triggers local inflammatory clearance.
Considered and rejected
Considered and rejected: Intratumoral delivery of free STING agonists was rejected due to rapid washout, lack of cell selectivity, and failure to address systemic occult metastases.
An Ultra-pH-Sensitive Logic Decodes Cancer Imaging and Immunotherapy · DSpace at UTSWMED
Tried and failed
immunogen delivery without membrane-anchoring tag applied to protein subunit vaccine delivery. Outcome: worse than baseline. Reason: rapid clearance from injection site resulted in negligible sustained follicular dendritic cell accumulation
Investigating the impact of vaccine formulations on humoral response via single-cell analysis · MIT
Tried and failed
low-dose soluble cytokine delivery applied to sustained macrophage phenotype repolarization. Outcome: no signal. Reason: rapid clearance and lack of sustained presentation fail to maintain persistent activation phenotypes
Macrophage-hitchhiking Anisotropic Microparticles for Therapeutic and Diagnostic Applications · MIT
Tried and failed
intra-articular injection for systemic drug delivery applied to bacteriophage systemic pharmacokinetic tracking. Outcome: no signal. Reason: circulating concentrations remained below the limit of detection following local intra-articular administration
Tried and failed
direct unencapsulated cell injection applied to joint cartilage repair in osteoarthritis. Outcome: worse than baseline. Reason: lack of biomaterial encapsulation reduced therapeutic retention and sustained chondroprotective paracrine signaling
Tried and failed
soluble ligand delivery in culture medium applied to progenitor cell differentiation. Outcome: no signal. Reason: ligand required mechanical tension or clustering via substrate immobilization to effectively trigger receptor signaling
Tried and failed
uncoated protein nanoparticle delivery applied to intranasal mucosal vaccination. Outcome: worse than baseline. Reason: lack of mucoadhesive or mucodiffusive coatings led to rapid clearance and poor long-term systemic humoral responses
Surface Engineering of Protein Nanoparticles for Intranasal Delivery · Georgia Tech
Considered and rejected
Considered and rejected: Unmodified/non-PEGylated nanoparticles were rejected for vaginal delivery applications due to inducing neutrophil infiltration into the vaginal lumen and showing inferior retention compared to PEG-functionalized mucus-penetrating particles.
Engineering placenta-tropic VEGF mRNA lipid nanoparticles for the treatment of pre-eclampsia · ScholarlyCommons at Penn
Delivery vehicles fail to overcome endothelial barriers and the blood-brain barrier
Passive nanoparticles and systemically administered small molecules lack the necessary transport mechanisms to traverse intact endothelial and blood-brain barriers. Even when permeabilizing strategies or dose escalation are employed, systemic routes fail to achieve the required barrier penetration compared to targeted regional delivery.
Tried and failed
baseline oral dosing control constraint applied to blood-brain barrier drug delivery. Outcome: no signal. Reason: dosage limit was too low to cross the blood-brain barrier and induce target phase shift
Tried and failed
systemic intravenous delivery of permeabilizing agent applied to blood-brain barrier opening for drug delivery. Outcome: worse than baseline. Reason: intravenous administration yields substantially lower barrier permeabilization and contrast enhancement than targeted intra-arterial delivery
From the body to the brain: Studying drug delivery and physiological interactions using MRI · MIT
Tried and failed
intravenous delivery of free synthetic microdevices applied to blood-brain barrier crossing to brain. Outcome: no signal. Reason: Free microdevices cannot cross the intact blood-brain barrier without cellular carrier mediation.
Tried and failed
unconjugated nanoparticle delivery across endothelial barriers applied to in vitro trans-endothelial migration. Outcome: no signal. Reason: passive particles lack active biological transport mechanisms to effectively cross the endothelial barrier
Considered and rejected
Considered and rejected: Orthotopic brainstem xenograft delivery of navitoclax was rejected in favor of a subcutaneous flank model due to navitoclax's inability to cross the intact blood-brain barrier.
Identifying the Mechanisms Behind Radiation Resistance in Treatment Naïve Diffuse Intrinsic Pontine Glioma Models · ResearchWorks
Left open by the authors
Problems the authors named and did not get to.
Left open
Improve the porosity-permeability relationship accuracy within biphasic deformation models for brain tissue drug delivery. Blocker: None
A mathematical framework for mechanically controlled brain drug delivery · Imperial
Left open
Deliver therapeutic mRNA including CRISPR/Cas9 to the brain using lipid nanoparticles. Blocker: Requires a wet lab, chemical synthesis, microfluidic equipment, and in vivo animal models for brain delivery.
Development of Chemically-Defined Platform Materials for Localized Delivery of RNA Therapeutics · MIT
Left open
Model drug delivery mechanisms including aerosol flow rate, delivered volume, payload release kinetics, and environmental interactions within the nanoparticle selection framework. Blocker: None
Left open
Investigate delivery methods to transport alpha-Synuclein targeting DNA aptamers across the blood-brain barrier in vivo. Blocker: Requires a wet lab, animal models, and in vivo delivery assays.
Left open
Synthesize varying size drug delivery vehicles and evaluate differential targeting of tissue-migratory versus lymph node-resident antigen-presenting cells. Blocker: Requires wet lab facilities for nanoparticle synthesis and in vivo/in vitro immunological testing
Engineered Nanotechnology for the Delivery of Cancer Immunotherapies to Lymph Nodes to Modulate Anti-Tumor T Cell Immunity · Georgia Tech
Left open
Develop in vitro and in vivo delivery strategies for DdCBEs to evaluate therapeutic potential in mitochondrial disease models. Blocker: Requires wet lab, cell cultures, and animal disease models for delivery experimentation
Precision Editing of Nuclear and Mitochondrial Genomes · Harvard
Left open
Apply the DEAEMA-based nanoparticle delivery system to treat glioblastoma multiforme, colorectal, breast, or liver cancer. Blocker: Requires wet lab synthesis of nanoparticles and biological testing on cancer cell lines or animal models
Polycationic nanoparticles for microRNA delivery in neuroblastoma · UT Austin
Left open
Evaluate mRNA delivery by barcoded lipid nanoparticles to intratumoral immune cell subtypes in immunocompetent mice with spontaneous tumors. Blocker: Requires wet lab facilities, barcoded LNP formulations, and in vivo animal tumor models
Translational Design of Lipid Nanoparticles (LNPs) to Deliver mRNA Therapies to Solid Tumors and to the Lungs · Georgia Tech
Left open
Investigate in vivo immune responses and neutralizing antibody formation after intra-articular versus systemic delivery of phage vB_SepM_Alex. Blocker: Requires wet lab facilities, in vivo animal models, and biological assays for immune response/antibody titration
Left open
Test treatment-relevant bolus dosing schedules or targeted delivery methods of dexamethasone on cartilage explants instead of continuous media replacement. Blocker: Requires a wet lab, cartilage explants, drug delivery systems, and LC-MS/MS proteomics equipment
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