Library · Biology & lab methods
What Vaccine Delivery & Formulation got wrong, from 42 theses
Summary written by a model from the records below: The records detail formulation and delivery obstacles encountered during vaccine development, encompassing lipid nanoparticle failures, carrier instability, and adverse adjuvant interactions. They also show how suboptimal delivery routes and complex nanocarrier designs frequently underperformed standard adjuvanted benchmarks or caused localized physical and physiological complications. 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.
Emulsion hydrogel and solid matrix formulations suffer from physical instability and delivery clogging
Emulsion and hydrogel formulations frequently suffered from phase separation, excessive viscosity, aggregation, or premature clogging during syringe mixing and extrusion. In other cases, matrix drying destroyed viral vector infectivity, and polyphenol complexes failed to retain nucleic acid cargo at the injection site.
Tried and failed
incorporating methyl methacrylate in emulsion copolymerization applied to pH-responsive cationic nanogels. Outcome: unstable. Reason: formulations aggregated across the testing pH range during colloidal stability measurements
A biodegradable pH-responsive carrier system for targeted siRNA delivery in inflammatory bowel diseases and cancer · UT Austin · PhD
Considered and rejected
Considered and rejected: Rejected Titermax Gold Liquid adjuvant emulsions in favor of aluminum hydroxide (Alhydrogel) for InMAD immunizations due to poor subcutaneous absorption and dosing uncertainty
Development of Diagnostic Assays for Melioidosis, Tularemia, Plague and COVID19 · University of Nevada, Reno · PhD
Considered and rejected
Considered and rejected: Rejected direct syringe-loading of commercial Kineret into MAMC double emulsions due to emulsion destabilization caused by formulation excipients.
Cellular And Mechano-Active Material Approaches To Improve Disc Repair After Herniation · Penn · PhD
Considered and rejected
Considered and rejected: Rejected primary emulsion formulations containing 5% oil because they formed an insufficient number of emulsion droplets.
Ultrasound-Assisted Novel Double Emulsion Containing Grape Pomace Polyphenols as a Delivery System to Encapsulate Vitamin E and Omega-3 for Food and Dietary Supplement Applications · Carleton University · Master's
Considered and rejected
Considered and rejected: Rejected primary emulsion formulations with 1.5%–4% psyllium husk because high viscosity hindered secondary emulsification mixing.
Ultrasound-Assisted Novel Double Emulsion Containing Grape Pomace Polyphenols as a Delivery System to Encapsulate Vitamin E and Omega-3 for Food and Dietary Supplement Applications · Carleton University · Master's
Considered and rejected
Considered and rejected: Aqueous phase CAT-SiNP formulation was replaced with reverse emulsion due to poor colloidal stability and rapid aggregation leading to RES clearance.
Hybrid Enzyme-Loaded Silica Nanoparticles for Potential Therapeutic Applications · UT Southwestern · Doctorate
Considered and rejected
Considered and rejected: Rejected HEMA, PEGMA, MAAc, DMAEMA, and Acrylamide in PVA semi-IPN formulation due to precipitation, excessive viscosity, low photoreactivity, or intrinsic toxicity.
Development and fabrication of self-healing hydrogels via vat photopolymerization 3D printing technology · Politecnico di Torino · PhD
Tried and failed
polyphenol-mediated depot formation for local retention applied to oligonucleotide adjuvant delivery. Reason: polyphenol complexation failed to retain oligonucleotide cargo at injection site unlike protein antigens
Engineering translational vaccine delivery systems with the polyphenol tannic acid · MIT · PhD
Tried and failed
controlled ambient humidity drying of polymer matrices applied to solid-state viral vector formulations. Outcome: unstable. Reason: sorption-desorption cycling and water movement caused complete loss of viral infectivity despite returning to baseline moisture
Formulation, bioprocessing, and manufacturing of viral vectors in unique dosage forms · UT Austin · PhD
Tried and failed
dual-syringe delivery of fast-gelling hydrogel precursor applied to in situ hydrogel formulation. Reason: gelation occurred too rapidly inside the mixing nozzle, causing immediate clogging and preventing injection
From heterotopic ossification to fracture healing: identifying and delivering adjuvants to modulate bone formation · Imperial · PhD
Tried and failed
direct ink writing of polymer solutions applied to viscoelastic hydrogel ink formulation. Reason: low concentration loses shape fidelity while high concentration causes nozzle clogging
Multiscale design of bioadhesive platforms for next-generation applications in surgery and healthcare · MIT · PhD
Synthetic nanocarriers and complex display platforms underperform conventional vaccine benchmarks
Engineered nanoparticles, modified saRNA variants, and display platforms frequently failed to boost antibody titers or match protection compared to standard soluble proteins or commercial vaccine baselines. Furthermore, co-delivering multiple antigens or using uncoordinated adjuvant dosing schedules triggered antigenic competition and impaired germinal center responses.
Tried and failed
immunization with soluble and uncoated protein nanoparticles applied to inducing cellular immune response. Outcome: no signal. Reason: antigen presentation without surface coating or adjuvant failed to stimulate cellular immunity over baseline
Development and Immunological Evaluation of Protein-Based Nanoparticle Vaccines · Georgia Tech · PhD
Tried and failed
polyanhydride nanoparticle encapsulation in copolymer hydrogel applied to cross-strain influenza viral challenge. Outcome: did not generalise. Reason: formulation yielded only partial protection against stringent heterologous viral challenge in mice
Universal room-temperature stable influenza A nanovaccine · Iowa State · Master's
Tried and failed
nanoparticle adjuvant delivery with soluble antigen applied to humoral antibody response boosting. Outcome: no signal. Reason: initial antibody titers failed to replicate or amplify following a booster administration
Evaluating the Effects of Particle-Delivered Combination Adjuvants on Antigen-Presenting Cells · Georgia Tech · PhD
Tried and failed
nanoparticle display of conserved viral fusion subunits applied to sub-variant viral challenge protection. Outcome: no signal. Reason: two doses with standard emulsion adjuvant induced insufficient immune response without stronger adjuvant or additional boost
Designing protein-based vaccines for broad protection against coronaviruses and influenza · Georgia Tech · PhD
Lost to a baseline
Cellulose-purified 0.1 µg saRNA formulations induced lower antibody titers and less protection against influenza challenge than unpurified unmodified saRNA
Optimization of the production and function of self-amplifying RNA vaccines · Imperial · PhD
Lost to a baseline
Stabilized flagellin nanoparticle adjuvant yielded lower serum antibody titers against SARS-CoV-2 HexaPro than the Addavax control in mice.
Targeting the Innate Immune System Using Protein Design · University of Washington · PhD
Tried and failed
co-delivery of multiple antigens in nanoparticle formulations applied to dual-pathogen subunit vaccination. Outcome: worse than baseline. Reason: antigen competition or immunological interference reduced antigen-specific serum IgG titers relative to single-antigen formulations
Utilizing Combinatory Adjuvant-Loaded Chitosan-Derived Nanoparticles for a Joint SARS-CoV-2/Influenza Vaccine · Georgia Tech · PhD
Lost to a baseline
Conjugate vaccine OXY-CRM197 + Alum elicited higher IgG antibody titers than the lipid-PLGA hNP-based OXY-CRM197-hNP(Alum) formulation
Precision Adjuvant Design Enabling Tailored Nanoparticle Immunization Platforms for Oxycodone and Other Substance Abuse Vaccines · Virginia Tech · Doctorate
Lost to a baseline
All PBAE formulations failed to elicit detectable N or S1 serum IgG antibody responses in vivo, whereas gene gun (gold particles) elicited high antibody titers.
New variants of poly(beta amino esters) to enhance delivery of nucleic acid medicines · Nottingham · PhD
Tried and failed
bolus adjuvant with escalating dose antigen schedule applied to vaccine immune response induction. Outcome: worse than baseline. Reason: asynchronous delivery failed to coordinate immune stimulation needed for germinal center and Tfh cell responses
Engineering kinetics of immunotherapies and vaccines · MIT · PhD
Lipid nanoparticle and liposome formulations fail due to poor encapsulation cytotoxicity or premature release
Lipid nanoparticle formulations suffered from poor nucleic acid encapsulation efficiency, vehicle cytotoxicity, and premature payload leakage caused by unfavorable lipid choices or non-optimal charge ratios. Additionally, targeting ligand modifications and in vitro screening protocols failed to translate into effective in vivo biodistribution or delivery.
Tried and failed
nanoparticle formulation at low lipid to cargo ratio applied to lipid nanoparticles encapsulating nucleic acids. Outcome: worse than baseline. Reason: insufficient lipid mass ratio resulted in poor cargo encapsulation efficiency
Development of Lipid Nanoparticles for RNA Delivery to Hematopoietic Stem Cells and Development of Alternative Model Systems for Nanoparticle Discovery · 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
Tried and failed
permanently charged cationic lipid substitution in nanoparticles applied to RNA delivery formulations. Outcome: worse than baseline. Reason: produced significantly lower transfection expression compared to degradable ionizable lipid benchmarks
Development of Chemically-Defined Platform Materials for Localized Delivery of RNA Therapeutics · MIT · PhD
Tried and failed
in vitro screening to predict in vivo delivery applied to lipid nanoparticle nucleic acid formulations. Outcome: did not generalise. Reason: In vitro delivery efficacy showed no correlation with in vivo delivery across hundreds of formulation variants
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 C3 LNP formulation at 20:1 N:P ratio despite higher in vitro delivery due to enhanced cytotoxicity and excess free ionizable lipid.
IONIZABLE LIPID NANOPARTICLES FOR IN UTERO GENE EDITING OF CONGENITAL DISEASE · Penn · 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 DOPE-dominated lipoplex formulations for in vivo gene delivery due to hexagonal phase-induced premature cargo release.
Advances in lipopolyplexes as efficient non-viral carrier for nucleic acid delivery Fortschritte bei Lipopolyplexen als effiziente nicht-virale Träger für die Übertragung von Nukleinsäuren · University of Marburg · PhD
Adjuvant additions cause immunological interference storage instability or severe tissue toxicity
Supplementing vaccines with certain adjuvants or small-molecule drugs dampened mucosal IgA responses, reduced neutralizing antibody titers, or actively suppressed CD8+ T cell responses. Other adjuvant formulations suffered binding losses upon storage or caused severe local injection-site nodules, inflammation, or systemic toxicity.
Lost to a baseline
Nanoparticle vaccine without drugs (OVA-E no DRUG) yielded higher Ova-specific total IgG and IgG1 titers than the formulation with encapsulated AICAR and rapamycin (p = 0.003)
Modulation of adaptive immunity through acute exercise, metabolism-targeting pharmacological agents, and chronic exercise training · Iowa State · PhD
Tried and failed
co-delivering TLR7 agonist adjuvant with mRNA vaccine applied to lipid nanoparticle mRNA vaccine formulation. Outcome: worse than baseline. Reason: failed to increase antibody titers and actively suppressed CD8+ T cell immune responses
Next-Generation Lipid Nanoparticle Formulations for Non-Liver Delivery of Nucleic Acid-Based Therapies and Vaccines · Georgia Tech · PhD
Tried and failed
alum adjuvant supplementation applied to mucosal and systemic antibody induction. Outcome: worse than baseline. Reason: alum dampened mucosal IgA response, impairing protection
The development of humoral breadth and protection against influenza · Harvard · PhD
Tried and failed
combining TLR agonist with alum adjuvant applied to protein subunit nanoparticle vaccine immunization. Outcome: worse than baseline. Reason: CpG addition unexpectedly reduced target-specific binding and neutralizing antibody titers compared to alum alone
RBD-HBsAg conjugated virus-like particle vaccine protects rhesus macaques from SARS-CoV-2 challenge · Harvard · Master's
Lost to a baseline
Preclinical adjuvant Sigma Adjuvant containing MPLA failed to activate lymphoid stromal cells as strongly as Alum supplemented directly with LPS.
TLR signalling alters the phenotype and function of lymphoid fibroblasts and impacts vaccination · Imperial · PhD
Lost to a baseline
RBD-VLP formulated with alum + CpG 1018 elicited lower binding antibody titers and ~30% less human ACE2 binding than the formulation with alum alone after storage.
Considered and rejected
Considered and rejected: Rejected aluminum hydroxide adjuvant in transdermal/pulmonary formulations due to skin irritation, nodule formation, and incompatibility with spray-freeze drying
Microneedle patches for hepatitis B vaccination · Boston University · Master's
Considered and rejected
Considered and rejected: Replacing Sigma Adjuvant System (SAS) with aluminum hydroxide (alum) adjuvant in the longitudinal stepwise immunization study due to severe SAS-induced lethality and glomerulonephritis in VH1-2/LCL mice.
Vaccine responses in the context of impaired self-tolerance · Harvard · PhD
Mismatched delivery routes and injection sites fail to generate protective localized immune responses
Administering vaccines via intramuscular or uncoated intranasal routes frequently failed to induce protective mucosal IgA or localized tissue-resident cellular immunity. Other non-standard routes, such as intra-tracheal or multi-site plasmid administrations, were abandoned due to procedural impracticality, poor distribution, or delayed seroconversion.
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
Tried and failed
intramuscular vaccination to induce mucosal antibody responses applied to respiratory viral mucosal immunity. Outcome: no signal. Reason: intramuscular delivery failed to boost or maintain long-term virus-specific mucosal IgA levels
Immediate and delayed immune and inflammatory responses to COVID-19 · Imperial · PhD
Lost to a baseline
Adjuvant-free dissolvable MNP group produced lower absolute antibody titers in rhesus macaques than control intramuscular injection of adjuvanted vaccine
Microneedle patches for hepatitis B vaccination · Boston University · Master's
Lost to a baseline
Intranasal immunization with Flu-Q11 formulations produced less dramatic viral load reduction than subcutaneous immunization.
Designing Multi-Epitope Supramolecular Nanofiber Vaccines for Autoimmunity and Infectious Disease · Duke · PhD
Considered and rejected
Considered and rejected: Intranasal route for QIV influenza vaccination was discarded because it did not improve T cell response compared to intraperitoneal application in the established mouse model.
Considered and rejected
Considered and rejected: Rejected intra-tracheal vaccination route for human translation due to procedural impracticality and uneven lung distribution compared to aerosol/intranasal delivery
The systemic-prime, mucosal-boost vaccine regimen for protection against respiratory viruses · Oxford · PhD
Considered and rejected
Considered and rejected: Aerosol route of BCG administration for practical field vaccination in calves (rejected in favor of s.c. administration due to aerosol inoculation being time-consuming and labor-intensive)
Functional and epigenetic aspects of BCG-induced trained immunity in bovine innate immune cell populations · Iowa State · PhD
Left open by the authors
Problems the authors named and did not get to.
Left open
Screen alternative ionizable lipids to replace DOTAP in lipid nanoparticles for protein delivery without causing in vivo toxicity or clotting. Blocker: Requires wet lab microfluidic formulation, in vitro encapsulation assays, and in vivo toxicity/clotting testing.
LIPID NANOPARTICLES ALLOW INTRACELLULAR PROTEIN DELIVERY FOR MODULATION OF DIFFICULT THERAPEUTIC TARGETS · Penn · PhD
Left open
Evaluate how RNA design and LNP formulations impact antigen and inflammatory kinetics in mRNA vaccines. Blocker: Requires a wet lab to formulate lipid nanoparticles (LNPs), design RNA sequences, and measure in vivo or in vitro kinetics.
Engineering kinetics of immunotherapies and vaccines · MIT · 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
Evaluate scFv and VHH ligand formats lacking Fc regions for targeting CD117 lipid nanoparticles. Blocker: Requires wet lab facilities, microfluidic formulation equipment, protein engineering, and in vivo/in vitro RNA delivery assays.
Left open
Test therapeutically relevant nucleic acid payloads formulated in lipid nanoparticles in an in vivo atherosclerosis mouse model. Blocker: Requires wet lab facilities, microfluidic LNP formulation, and in vivo animal disease models
Design and Formulation Optimization of Lipid Nanoparticles Carrying MRNA to the Heart and the Pancreas · Georgia Tech · PhD
Left open
Develop lipid nanoparticle-based mRNA delivery strategies for Cas9-retron genome editing systems. Blocker: Requires a wet lab for lipid nanoparticle formulation, mRNA synthesis, and in vitro/in vivo delivery assays
Discovery of novel systems for genome editing · UT Austin · PhD
Left open
Evaluate in vivo biodistribution and systemic cytokine cascade leakage of LbL nanoparticles across heterogeneous tumor phenotypes. Blocker: Requires wet-lab facilities, animal models, and physical nanoparticle formulations.
Layer-by-Layer Nanoparticles for Cytokine Delivery · MIT · PhD
Left open
Load cGAMP-STINGΔTM vaccine component onto the LbL-coated microneedle and evaluate its therapeutic efficacy in mouse melanoma models. Blocker: Requires wet lab drug formulation, microneedle fabrication, and in vivo mouse melanoma experiments
Layer-by-layer coated microneedles for cancer immunotherapy · MIT · PhD
Left open
Develop microneedle patches with time-changing degrading patterns to indicate elapsed time post-administration. Blocker: Requires wet-lab polymer formulation, microneedle fabrication, and physical degradation testing
Microscale polymeric-based technologies for controlled vaccine delivery · MIT · PhD
Left open
Design de novo protein scaffolds or multi-component nanoparticle displays across sequential immunizations to minimize off-target anti-scaffold antibody responses. Blocker: Requires wet lab protein engineering, nanoparticle formulation, and in vivo immunization assays
Rationally designed immunogens enable immune focusing following SARS-CoV-2 spike imprinting · Harvard · PhD
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 - Sachin Haresh Bhagchandani · MIT · PhD · 2023
Engineering kinetics of immunotherapies and vaccines - Yuqing Zhang · Carleton University · Master's · 2023
Ultrasound-Assisted Novel Double Emulsion Containing Grape Pomace Polyphenols as a Delivery System to Encapsulate Vitamin E and Omega-3 for Food and Dietary Supplement Applications - Yu An Lin · Boston University · Master's · 2021
Microneedle patches for hepatitis B vaccination - 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 - Dennis Shi · MIT · PhD · 2025
Development of a targeted lipid nanoparticle platform for in vivo RNA delivery to hematopoietic stem and progenitor cells - Yuanzhi Bian · Virginia Tech · Doctorate · 2025
Precision Adjuvant Design Enabling Tailored Nanoparticle Immunization Platforms for Oxycodone and Other Substance Abuse Vaccines - Ester Álvarez Benedicto · UT Southwestern · 2025
Engineering Lipid Nanoparticle-Mediated Delivery of Nucleic Acids to Lymphoid Organs and Immune Cells - Elisa Schrader · Georgia Tech · PhD · 2024
Design and Formulation Optimization of Lipid Nanoparticles Carrying MRNA to the Heart and the Pancreas - Ryan Zenhausern · Georgia Tech · PhD · 2024
Development of Lipid Nanoparticles for RNA Delivery to Hematopoietic Stem Cells and Development of Alternative Model Systems for Nanoparticle Discovery - Sarah J. Wu · MIT · PhD · 2024
Multiscale design of bioadhesive platforms for next-generation applications in surgery and healthcare - Ivan S. Pires · MIT · PhD · 2024
Layer-by-Layer Nanoparticles for Cytokine Delivery
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