Chapter Four · failure evidence
What Nanocarrier Drug Loading & Release got wrong, from 28 dissertations
The evaluated records detail experimental attempts to design, load, and control drug release from nanocarriers and microscale encapsulation vehicles. Across these studies, researchers frequently encountered challenges including premature leakage, sluggish or incomplete release kinetics, insufficient loading capacity, and rapid clearance in physiological environments. These records come from PhD theses at 13 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.
Premature cargo leakage and uncontrolled burst release prevent stable delivery
Nanocarriers and encapsulation matrices suffered from membrane permeability, agglomeration, or inadequate complexation that caused rapid burst release of their payload. These issues resulted in poor small molecule retention, premature unloading in plasma, and rapid drug loss in gastrointestinal conditions.
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
Considered and rejected
Considered and rejected: 80% sirolimus nanofiber loading target was rejected in favor of 40% loading due to a pronounced burst release occurring within the first 24 h.
ENGINEERING NANOSTRUCTURED MEDICAL DEVICES AND FORMULATIONS FOR IMPROVING SURGICAL OUTCOMES · JScholarship
Considered and rejected
Considered and rejected: Rejected using single wall material (such as maltodextrin alone) due to quick gastrointestinal release, deficient emulsification, and lower encapsulation efficiency.
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
Tried and failed
polysaccharide surface coating for controlled release applied to mesoporous inorganic nanoparticles. Outcome: unstable. Reason: coating induced nanoparticle agglomeration and triggered non-selective burst release of loaded ions
Inorganic nanoparticles for cancer therapy · Imperial
Tried and failed
in situ albumin-binding maleimide prodrug delivery applied to cytotoxic drug delivery. Outcome: unstable. Reason: rapid premature payload release in plasma compared to preformed ex vivo conjugates
Albumin as a drug delivery carrier to overcome biological barriers in cancer · UT Austin
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
Excessively slow or incomplete drug release impairs therapeutic performance
Nanoparticles, microparticles, and gels exhibited restricted diffusion, excessive polymer hydrophobicity, or dense crosslinking that hindered payload release. This sluggish release led to lower cytotoxicity than free drugs, incomplete cumulative drug recovery, or poor responsiveness to environmental triggers.
Lost to a baseline
PGC-PTX + PTX NPs had higher in vitro IC50 values (14.1 to 67.2 ng/mL) across mesothelioma cell lines compared to free PTX (1-10 ng/mL) due to slow sustained drug release.
Tried and failed
two-photon polymerisation of microscale drug delivery capsules applied to sustained macromolecule release. Outcome: no signal. Reason: pore geometry and polymer degradation kinetics prevented diffusion and release of loaded protein cargo
Nanoscale biodegradable printing for designed tuneability of vaccine delivery kinetics · Imperial
Tried and failed
block copolymer blending for erosion rate acceleration applied to polymeric core-shell microparticle cap. Outcome: worse than baseline. Reason: Block copolymer blending did not accelerate release timing compared to physically doping homopolymer.
Microscale polymeric-based technologies for controlled vaccine delivery · MIT
Lost to a baseline
Curcumin-loaded Poly ε-Caprolactone nanofibers reached only ~50% cumulative release after 30 days, compared to other polymer systems reaching almost 100%.
Curcumin as endometriosis treatment: efficacy, drawbacks, and future perspectives · OpenBU
Considered and rejected
Considered and rejected: Rejected longer ω-carboxyalkanoate linkers (adipate or longer via benzyl-protected acid chlorides or cross-metathesis) because excessive hydrophobicity caused polymers to swell without dissolving, yielding poor drug release.
Mixed Polysaccharide Esters for Amorphous Solid Dispersion Oral Drug Delivery Vehicles · Virginia Tech
Considered and rejected
Considered and rejected: Binary liposome compositions BSM:CH (50:50 wt%) and PC:CH (50:50 wt%) were rejected in favor of the ternary BPC formulation (BSM:PC:CH 33:33:33 wt%) due to lower toxin-triggered release responsiveness
Engineering catalytic gold nanoclusters and nanovesicles for detection of disease · Imperial
Tried and failed
intermediate charge ratio complexation in lipid nanoparticles applied to siRNA delivery and gene silencing. Outcome: worse than baseline. Reason: intermediate charge ratios exhibited slowest release kinetics, reducing downregulation efficacy
Lipid-based nanoparticles for drug delivery · UT Austin
Insufficient carrier loading capacity limits delivery and functional activity
Carriers failed to bind or encapsulate sufficient quantities of active agents due to low surface charge or restricted internal capacity. Consequently, released drug concentrations were too low for effective dosing, and low polymer-to-nucleic acid ratios prevented endosomal escape.
Considered and rejected
Considered and rejected: Abandoned polymersome encapsulation of antisense morpholinos for in vivo gene knockdown because released concentration was too low (~350 pmol/mL) to reach functional in vivo doses without aggregation.
Regulating Gene Expression With Light-Activated Oligonucleotides · Penn
Considered and rejected
Considered and rejected: Rejected 2nd gen sequential layering of P10PSH copolymer onto preformed AuNP-RNP because maximum polymer loading achieved only N/P 0.5, insufficient for endosomal escape.
Development of Third-Generation Gold Nanoparticles (CRISPR-AuNP) for Enhanced CRISPR Delivery to Hematopoietic Stem and Progenitor Cells · ResearchWorks
Tried and failed
unfunctionalized vertical nanostructures for intracellular delivery applied to nucleic acid transfection in primary immune cells. Outcome: no signal. Reason: lack of surface charge or functionalization prevented effective nucleic acid binding and intracellular release
Rapid clearance and loss of structural integrity undermine in vivo release control
Carrier formulations that showed sustained profiles in vitro failed to translate in vivo due to rapid clearance indistinguishable from controls. Additionally, bulk degradation led to non-linear release profiles and loss of mechanical integrity that prevented carrier retrieval.
Considered and rejected
Considered and rejected: Rejected bulk-degrading polymer micro/nanoparticles, gels, and films due to non-linear release, loss of mechanical integrity preventing retrieval, and rapid lymphatic clearance
Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment · MIT
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
Left open by the authors
Problems the authors named and did not get to.
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
Optimize CHIR99021 dosage and encapsulate it using nanoparticles, liposomes, or bioink conjugation for sustained controlled release. Blocker: Requires wet lab facilities for nanoparticle/liposome formulation, drug conjugation, and release kinetics assays.
3D Bioprinting of Perfusable Cardiac Patches to Treat Myocardial Infarction · Georgia Tech
Left open
Conduct in vivo and stimuli-responsive release testing of therapeutic cargo and MRI contrast agents from functionalised Type II nanogels. Blocker: Requires wet lab synthesis, biological materials, and in vivo animal testing facilities
Molecular and nanoscale agents for magnetic resonance imaging · Imperial
Left open
Quantify in vitro release kinetics of resveratrol encapsulated within donkey and bovine beta-casein micelles. Blocker: Requires wet lab equipment, purified beta-casein, and dialysis/chromatography apparatus for release assays
Encapsulation of bioactive nutraceutical compounds in donkey and bovine milk β-casein-based carriers · IRIS - UNICAM - prod
Left open
Test in vivo whether higher re-loading doses of free PROTAC enable non-covalent ADC re-loading in circulation. Blocker: Requires in vivo animal experiments and specialized wet lab facilities
Left open
Assess transported PDF models, beta-PDF intermittency factor corrections, or LES subfilter closures against the reacting jet DNS dataset. Blocker: Requires access to the proprietary or unreleased DNS flow field dataset generated in the thesis.
A reacting jet direct numerical simulation for assessing combustion model error · UT Austin
Left open
Perform systematic release studies of varying molecular weight and chemical cargo to characterize dynamic mesh size and hydrophilicity of SCRIBE resins. Blocker: Requires wet lab facilities, synthetic polymer chemistry, 2PP microprinting apparatus, and physical drug release assay capabilities
Nanoscale biodegradable printing for designed tuneability of vaccine delivery kinetics · Imperial
Left open
Develop and synthesize dendrimer-based nanomodulators targeting CXCR4 to encapsulate and release SDF-1α or AMD-3100. Blocker: Requires a wet chemistry and biomaterials laboratory to synthesize dendrimers and test drug release kinetics.
Left open
Test non-pH responsive, PBS-soluble anticancer drugs for encapsulation and release in pH-responsive methacrylic polymersomes. Blocker: Requires a wet chemistry and biology lab to synthesize polymersomes and perform drug encapsulation/release assays
Self-assembled block copolymers: micelles, polymersomes and gels · Imperial
Left open
Synthesize pH-responsive nanogels incorporating an enzyme-degradable peptide crosslinker (such as MMRRRKK) to enhance protein release in the small intestine. Blocker: Requires wet lab chemical synthesis (inverse emulsion polymerization) and biological degradation testing
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