How I would approach a research question.

Can selective target degradation outperform occupancy-based inhibition in a defined disease state?

Working hypothesis. For a biologically validated, ligandable disease-state regulator, inducing selective proteasomal degradation may produce a more durable functional response than reversible inhibition at matched free intracellular exposure. This is contingent on E3-ligase expression, ternary-complex geometry, substrate resynthesis and the cellular disease state.

First experimental system

Use a validated and tractable model such as BRD4-dependent transcriptional signalling as a method-development benchmark, then select a disease-relevant target only after perturbation experiments establish causal dependence in the relevant cells. Start with commercially validated reference degraders or established literature chemistry, not an untested claim of novel drug discovery.

Design and chemistry

• Compare a target-binding ligand, an E3-recruiting PROTAC and matched non-degrading controls. Map linker attachment sites and physicochemical properties.
• Explore modular click or other bioorthogonal coupling only if it can deliver analytically verified conjugates with appropriate permeability, stability and target engagement. Click chemistry is an engineering option, not proof of biological activity.
• Define target engagement and degradation independently using orthogonal protein assays, time-course measurements, dose-response curves and proteomic selectivity where possible.

Mechanistic and pharmacological discrimination

Test proteasome and E3 dependence with competition or pathway controls, study degradation kinetics and target recovery after washout, and compare responses at measured unbound exposure. Use genetic knockdown and rescue as complementary evidence for target dependence. Where a compound changes phenotype without verified degradation, retain off-target activity or conventional inhibition as alternative explanations.

Decisive criterion

The programme advances only if target engagement, selective degradation and a disease-relevant phenotype align at tolerable exposures. A lower immunoblot band alone is insufficient. A negative result may identify an E3-ligase or transport limitation and motivate a revised recruiter, linker or target, rather than an indiscriminate analogue library.

Primary precedents: Winter et al., Science (2015) ↗; Lu et al., Chemistry & Biology (2015) ↗.

Does aptamer-directed, microfluidically prepared carrier design increase productive circular-RNA expression in injured pulmonary epithelium?

Working hypothesis. If an accessible epithelial surface marker is validated as enriched in a relevant injury state, an appropriately stabilized aptamer-ligated lipid carrier might improve functionally productive intracellular delivery of a reporter-encoding circular RNA compared with the same untargeted carrier. Surface binding, cellular uptake, translation and tissue recovery must be measured as distinct endpoints.

Feasibility phase: disentangle cargo from carrier

• Choose a protein-coding circular-RNA reporter with independently verified circularization, translation competence and impurity profile; compare with a matched linear-RNA control where feasible.
• Prepare well-characterized lipid carriers with controlled microfluidic mixing and benchmark against a non-microfluidic or conventional formulation under matched lipid composition, cargo dose and purification conditions.
• Verify particle-size distribution, encapsulation, cargo integrity and colloidal stability before and after the intended route of administration. If nebulization is pursued, separately quantify emitted dose and aerodynamic behavior.

Targeting and biological validation

What earlier work does and does not establish: Katie Ryan and colleagues have tested nebulized siRNA lipoplexes and lipid nanoparticles, including how aerosol generation affects formulation and functional silencing. That provides a route-specific formulation benchmark, not evidence that a circular-RNA cargo has the same stability, intracellular release or translated-protein output. Jing Yong Ye and colleagues have reported modified-aptamer optical biosensing: relevant to recognition, stability and assay design, but not proof that such an aptamer can deliver circular RNA to airway cells. The independent research question proposed here is whether a justified ligand, RNA architecture and formulation jointly improve productive function under disease-relevant exposure.

Use a receptor-binding aptamer only after validating receptor accessibility and binding under disease-relevant conditions. Compare targeted carriers with untargeted carriers and a nonbinding/scrambled aptamer, controlling for surface charge and ligand density. Quantify uptake and endosomal localization, but prioritize translated reporter signal per administered and cell-associated dose. Measure cytotoxicity, innate immune activation and barrier integrity.

Model choice and pharmacology

Begin in a reproducible human airway-cell system, and progress to an air–liquid interface culture or perfused airway-on-chip only when barrier composition, cellular heterogeneity and injury reproducibility are qualified. Evaluate spatial delivery, exposure duration, expression kinetics and a predefined functional outcome. A fluorescence-positive particle is not proof of productive cytosolic release.

Pathway choice must precede carrier optimization

A candidate such as BMPR2–SMAD1/5/9 signalling in pulmonary vascular dysfunction offers a concrete example of a restorative question, but published BMPR2 mRNA results do not demonstrate the efficacy of circular RNA. Equally, Rasha Alshaikh’s S1P/siponimod studies concern receptor pharmacology and ocular vascular exposure; they provide an example of how to test a pharmacological mechanism and a controlled-release system, not an already validated target for pulmonary circRNA. A clinically relevant programme would choose one causally implicated pathway and establish the correct intervention before comparing advanced nanocarriers.

Decisive criterion

Progress requires a reproducible gain in functional expression without unacceptable barrier injury or inflammatory signalling, attributable to the aptamer rather than lipid composition or assay artefact. Otherwise prioritize cargo purity, endosomal escape and biophysical stability over further targeting complexity.

Primary precedents: Nature Communications (2024), organ-targeted expression ↗; Nature Communications (2024), aerosol stability ↗; CircRNA LNP formulation in preclinical vaccination (2025) ↗.

Related experimental precedents: Ryan-group siRNA nebulization ↗ · Ye-group modified-aptamer sensor proceedings ↗ · Alshaikh-group S1P pharmacology ↗. These papers investigate different cargos, routes or tissue models.

Scientific fit comes before any preferred technology.

These examples are options for discussion, not conditions I place on a future laboratory. My preference is to identify one tractable scientific uncertainty within a group's established programme and investigate it thoroughly. That could be a chemical-synthesis challenge, an experimentally testable signalling mechanism, the disposition of a drug formulation or a measurement problem in physiology. A strong doctorate should not depend on using a PROTAC, aptamer, circular RNA or pulmonary disease model simply because I have written about them.

My longer-term interest is in how molecular and engineered systems affect biology. That may be pursued through fundamental chemistry, engineering methods, mechanism-focused biological research or translational pharmacology. Where a therapeutic is the goal, I want to understand its chemistry, exposure and functional consequences; where the work is more fundamental, robust experimental or theoretical knowledge is an achievement in itself.

See my completed experimental record ↗ · Read the broader research agenda ↗