Library · Biology & lab methods
What Targeted Drug Delivery Systems got wrong, from 43 theses
Summary written by a model from the records below: The records evaluate various targeted drug delivery systems across physiological barriers, carrier formulations, and administration routes. Many approaches encountered significant hurdles including rapid clearance from target sites, structural instability of delivery carriers, impaired pulmonary distribution, and ineffective cellular uptake. These records come from graduate theses, 2021 to 2026, each labeled with its degree where the repository states it, and 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.
Plus 10 problems the authors left open, listed at the end.
Failure modes, by theses reporting them
Select a mode to jump to its records.
Rapid clearance and lack of retention undermine unencapsulated or unmodified therapeutics
Unprotected small molecules, soluble cytokines, and unmodified nanoparticles frequently suffer from rapid tissue clearance and fail to accumulate in target sites such as lymph nodes or joints. Systemic and intra-articular administration of unencapsulated payloads leads to undetectable circulating concentrations, severe off-target organ clearance, and toxic inflammatory responses.
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 · PhD
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 · PhD
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 · UT Southwestern · Doctorate
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 · PhD
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 · PhD
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 · PhD
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
DEFINING BACTERIOPHAGE DOSING AND PHARMACOKINETIC PARAMETERS FOR STAPHYLOCOCCUS EPIDERMIDIS PROSTHETIC JOINT INFECTION · Harvard · Master's
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
Identification of cellular attributes that relate to the therapeutic efficacy of Mesenchymal Stromal Cells for treatment of Osteoarthritis · Georgia Tech · PhD
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 · PhD
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 · PhD
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 · Penn · PhD
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 · PhD
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 · PhD
Carrier instability, membrane leakage, and processing defects disrupt formulation delivery
Nanoparticles and liposomes often fail due to premature payload leakage, shell dissolution in acidic conditions, or physical disruption during microfluidic scale-up. In addition, mechanical issues such as nozzle clogging during printing and poor vehicle viscosity cause severe loss of injectability and reduced bioavailability.
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
Systematic engineering of controlled, localized oligonucleotide delivery systems for wound angiogenesis · MIT · PhD
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
Synthesis and Characterization of Liposomes for pH-triggered Delivery of Hydrophilic and Lipophilic Bioactives · Cornell · PhD
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 · PhD
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
Layer-by-Layer Nanoparticles for Cytokine Delivery · MIT · PhD
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 · PhD
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 · PhD
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 · UT Southwestern
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 · PhD
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 · Nottingham · PhD
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 · PhD
Suboptimal lipid and vector designs impair intracellular delivery and nucleic acid transfection
Neutral, anionic, or poorly matched cationic lipid nanoparticle compositions fail to achieve efficient mRNA transfection or cellular delivery compared to optimized controls. Similarly, viral and non-viral vectors frequently suffer from low transduction efficiency, batch variability, or misdirected organ biodistribution.
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.
LIPID NANOPARTICLES ALLOW INTRACELLULAR PROTEIN DELIVERY FOR MODULATION OF DIFFICULT THERAPEUTIC TARGETS · Penn · PhD
Lost to a baseline
Cationic lipid library (e.g., X10-C12) and PEG-mediated RNP delivery achieved parity but failed to surpass control methods (TransIT-2020 and dried protein) in preliminary biolistic Cas9 RNP editing
Improving biolistic delivery for DNA and protein systems in plants · Iowa State · PhD
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 · PhD
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 · PhD
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 · PhD
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 · UT Southwestern · Doctorate
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 · PhD
Aerosolization and physical constraints hinder targeted pulmonary drug delivery
Inhalable formulations and nebulized nanoparticles frequently fail because concentrated suspensions clog delivery mesh pores or produce particle sizes too large for deep lung delivery. Furthermore, aerosol nebulization and intravenous routes achieve substantially lower pulmonary concentrations than local instillation or nasal delivery.
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
Engineering Protease Activity Sensors and Machine Learning Methods to Detect and Characterize Disease · Harvard · PhD
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 · PhD
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 · PhD
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
Construction of a highly potent inhalable microparticles combination therapy to treat pulmonary tuberculosis · Imperial · PhD
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 · PhD
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 · Politecnico di Torino · PhD
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 · PhD
Targeting ligands and surface conjugation fail to outperform unconjugated or full antibody controls
Conjugating single-chain antibody fragments or lower-density peptide blocks to nanoparticles often fails to improve cellular uptake or delivery potency compared to full monoclonal antibodies. In other cases, conjugation does not enhance local retention over free therapeutics, and broad tissue inflammation can suppress delivery pathways entirely.
Tried and failed
cell-specific targeting and dose escalation applied to overcoming inflammation-reduced nanoparticle delivery. Outcome: no signal. Reason: Inflammation broadly suppressed delivery pathways regardless of vehicle targeting or higher dosing.
UTILIZING HIGH-THROUGHPUT IN VIVO NANOPARTICLE SCREENS TO IMPROVE DRUG DELIVERY · Georgia Tech · PhD
Lost to a baseline
scFv-conjugated LNP formulations failed to outperform monoclonal antibody (104D2 mAb) conjugated LNPs in delivery
Antibody-Conjugated Lipid Nanoparticles Could Enable Targeted Delivery to Long-Term Hematopoietic Stem Cells to Treat Blood Diseases · Harvard · Master's
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 · PhD
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 · Nottingham · PhD
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 · PhD
Tried and failed
polymeric nanoparticle delivery of antigen applied to immunocompromised metabolic syndrome models. Outcome: worse than baseline. Reason: nanoparticles failed to improve germinal center or antibody response compared to soluble antigen
Immune Organoids to Study Antigen Presentation · Cornell · PhD
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
Antibody-Conjugated Lipid Nanoparticles Could Enable Targeted Delivery to Long-Term Hematopoietic Stem Cells to Treat Blood Diseases · Harvard · Master's
Physiological transport barriers prevent delivery across vascular and blood-brain barriers
Oral dosing limits and systemic intravenous delivery prove inadequate to overcome the blood-brain barrier without targeted arterial delivery or cellular carrier mediation. Furthermore, unconjugated passive particles and concentrated drugs encounter steep diffusion barriers and lack the active transport mechanisms needed to cross endothelial layers.
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 · PhD
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
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 · PhD
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 · University of Washington · PhD
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 · PhD
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 · PhD
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
Design Tool Used for the Selection of Nanoparticle Drug Delivery Systems in the Treatment of Respiratory Diseases · Harvard · Master's
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 · PhD
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 · PhD
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 · PhD
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 · PhD
Left open
Optimize Anakinra dosing regimens and evaluate sustained drug delivery formulations to prolong joint residence time. Blocker: Requires wet lab formulation chemistry, in vitro release assays, or in vivo pharmacokinetic testing
Expanding Indications for Biologic Osteochondral Repair · Penn · PhD
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
DEFINING BACTERIOPHAGE DOSING AND PHARMACOKINETIC PARAMETERS FOR STAPHYLOCOCCUS EPIDERMIDIS PROSTHETIC JOINT INFECTION · Harvard · Master's
Who has worked on this
Authors of the public theses cited on this page, most-cited first.
- Sebastian Gonzalo Huayamares · Georgia Tech · PhD · 2023
Translational Design of Lipid Nanoparticles (LNPs) to Deliver mRNA Therapies to Solid Tumors and to the Lungs - Miranda Rubin Peer · Harvard · Master's · 2026
Antibody-Conjugated Lipid Nanoparticles Could Enable Targeted Delivery to Long-Term Hematopoietic Stem Cells to Treat Blood Diseases - Jason Young · Harvard · Master's · 2026
DEFINING BACTERIOPHAGE DOSING AND PHARMACOKINETIC PARAMETERS FOR STAPHYLOCOCCUS EPIDERMIDIS PROSTHETIC JOINT INFECTION - Shubham Yadav · MIT · PhD · 2026
Bridging the Invasiveness–Precision Gap: Autonomous Biohybrid Nanoelectronics Enable Surgery-Free Focal Neuromodulation - Afsane Radmandaghkand · Georgia Tech · PhD · 2023
Next-Generation Lipid Nanoparticle Formulations for Non-Liver Delivery of Nucleic Acid-Based Therapies and Vaccines - Paul A. Archer · Georgia Tech · PhD · 2022
Analysis of Nanomaterial Physiochemical Property Influences on Lymph Node Accumulation and Leukocyte Association - Lauren Faith Sestito · Georgia Tech · PhD · 2021
Engineered biomaterials for drug delivery and therapeutic modulation in lymphatic tissues - Zachary Thomas Bennett · UT Southwestern · Doctorate · 2026
An Ultra-pH-Sensitive Logic Decodes Cancer Imaging and Immunotherapy - LORENA PASERO · Politecnico di Torino · PhD · 2026
Particle Engineering via Spray Freeze-Drying for Pulmonary Drug Delivery Applications - Yiming Zhang · MIT · PhD · 2025
Investigating the impact of vaccine formulations on humoral response via single-cell analysis - Susan Thomas Varghese · Harvard · Master's · 2025
Design Tool Used for the Selection of Nanoparticle Drug Delivery Systems in the Treatment of Respiratory Diseases - Kelsey L Swingle · Penn · PhD · 2025
Engineering placenta-tropic VEGF mRNA lipid nanoparticles for the treatment of pre-eclampsia
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