Graduate Research Course · Medicinal Chemistry & Therapeutics Track
Disease & New Approaches
Mechanism of Delivery & Action — from logic-gated DNA nanorobots to in vivo CRISPR
Nine modules covering the mechanisms by which modern therapeutic modalities reach the right cell, the right target, and the right biochemical outcome. The course is organised by modality (how the drug works), not by disease, so that the principles generalise across oncology, genetic disease, neurology, and infectious disease.
About This Course
The last decade has seen the therapeutic toolbox expand from small molecules and antibodies to an entire new generation of precision modalities: logic-gated DNA-drug conjugates that release payload only when two or more biomarkers are simultaneously present; PROTACs and molecular glues that hijack the ubiquitin-proteasome system to degrade previously “undruggable” proteins; mRNA-LNP platforms that translate the COVID-19 vaccine stack into therapeutics for cancer, rare disease, and autoimmunity; CAR-T and in vivoCRISPR; and radio-ligand theranostics that pair diagnostic PET with matched therapeutic β/α-emitters.
Each module treats the biophysics and biochemistry of the modality in depth: binding kinetics, ternary complexes, hook effects, linker chemistry, endosomal escape, pharmacokinetic modelling, ADC payload release, AAV capsid engineering, radiochemistry, and the quantitative modelling required to predict clinical response. Python simulations run pharmacokinetic compartment models, ternary-complex titrations, Poisson-distributed CAR-T expansion, LNP size distributions, and dosimetry.
Cross-links: Biochemistry,Molecular Biology,Bioinformatics,Cell Physiology,Cytoskeleton,Biophysics.
Flagship Module · M1
Logic-Gated Drug Delivery via DNA-Drug Conjugates
A 100-nanometre DNA-origami barrel folded with 168 DNA staples, armed with 12 thrombin payload molecules and closed by a DNA hairpin — this is Douglas, Bachelet & Church’s (Science 2012) aptamer-gated nanorobot. The barrel opensonly when two surface markerssimultaneously bind matching aptamer hinges, releasing payload at the tumour with single-cell specificity.
M1 builds this up from the ground: DNA hybridization thermodynamics ΔG = ΔH − TΔS and the strand-displacement kinetic cascades of Seelig & Winfree, aptamer-SELEX selection, combinatorial AND/OR/NAND/XOR logic on DNA scaffolds (Benenson 2004 molecular computer, Qian 2011 four-bit square-root circuit), thresholded release with noise-tolerant logic levels, and the latest in vivowork on CAR-NK logic gating. Python simulations model hairpin opening kinetics, fraction-of-circuit-activated vs. two-input concentration, and the tumor-to-healthy selectivity ratio.
Key Equations
Hill Binding Isotherm
\( \theta = \frac{[L]^n}{K_d^n + [L]^n} \)
Ternary Complex (PROTAC)
\( K_{ternary} = \frac{[A\cdot P\cdot B]}{[A][P][B]} \)
DNA Hybridization
\( \Delta G^\circ = \Delta H^\circ - T \Delta S^\circ \)
ADC Payload Release
\( \frac{dC}{dt} = k_{int}\,[\text{ADC}] - k_{clear}\,C \)
CAR-T Expansion
\( \frac{dN}{dt} = rN\bigl(1 - N/K\bigr) \)
LNP Endosomal Escape
\( \eta_{esc} = f(\text{pKa}, [\text{H}^+], \text{lipid}) \)
Nine Modules
M0
The Druggable Genome & Modalities Landscape
Druggable target classes (~3 000 of 20 000 genes), small molecule → biologic → cell/gene therapy taxonomy, regulatory pathways FDA/EMA, modality-target fit matrix.
M1
Logic-Gated Drug Delivery via DNA-Drug Conjugates
DNA origami nanorobots (Douglas 2012), aptamer-gated release, AND/OR/NAND logic on DNA scaffolds, sense-and-release on tumour surface markers, thresholded triggering.
M2
PROTACs & Molecular Glues
Heterobifunctional degraders (POI-linker-E3), ternary complex kinetics, hook effect, CRBN/VHL/MDM2 E3 handles, molecular glues (thalidomide, indisulam), Arvinas ARV-471 estrogen receptor degrader.
M3
Antibody-Drug Conjugates
Kadcyla (T-DM1), Enhertu (T-DXd), linker chemistry (cleavable vs. non-cleavable), DAR optimisation, payload classes (auristatins, maytansinoids, calicheamicins, topo-I inhibitors), bystander effect.
M4
CAR-T & Cell Therapies
Kymriah (CD19), Yescarta, Abecma, Breyanzi; 1st/2nd/3rd/4th gen CARs; TRUCK (armored), gated CARs (AND/NOT logic), allogeneic CARs, NK and TCR-T therapies, CRS toxicity.
M5
mRNA Therapeutics & LNPs
LNP formulation (DLin-MC3, SM-102, ALC-0315), endosomal escape, modified nucleotides (Karikó ψU), self-amplifying mRNA (saRNA), circRNA, COVID-19 lessons, Moderna/BioNTech platforms.
M6
CRISPR Therapeutics
Cas9 mechanism, sgRNA design, delivery (AAV, LNP, electroporation), base editing (ABE/CBE Liu lab), prime editing, epigenome editing, in vivo Verve VERVE-102, Casgevy 2023 sickle-cell approval.
M7
AAV & Lentiviral Gene Therapy
AAV serotypes & tropism, capsid engineering (directed evolution, AAV-MaCPNS), Luxturna (RPE65 Leber), Zolgensma (SMN1 SMA), Hemgenix (factor IX haemophilia B), seroprevalence challenges.
M8
Theranostics & Radio-Ligand Therapy
Pluvicto (177Lu-PSMA-617), Lutathera (177Lu-DOTATATE), alpha-emitters (225Ac-PSMA, 223Ra Xofigo), paired diagnostic PET (68Ga-PSMA-11), companion diagnostics, personalized dosimetry.
Key References
- [1] Douglas, S. M., Bachelet, I. & Church, G. M. (2012). A logic-gated nanorobot for targeted transport of molecular payloads. Science, 335, 831–834.
- [2] Békés, M., Langley, D. R. & Crews, C. M. (2022). PROTAC targeted protein degraders: the past is prologue. Nature Reviews Drug Discovery, 21, 181–200.
- [3] Karikó, K. et al. (2005). Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification. Immunity, 23, 165–175.
- [4] Anzalone, A. V. et al. (2019). Search-and-replace genome editing without double-strand breaks or donor DNA (prime editing). Nature, 576, 149–157.
- [5] June, C. H. et al. (2018). CAR T cell immunotherapy for human cancer. Science, 359, 1361–1365.
- [6] Wang, D., Tai, P. W. L. & Gao, G. (2019). Adeno-associated virus vector as a platform for gene therapy delivery. Nature Reviews Drug Discovery, 18, 358–378.
- [7] Sartor, O. et al. (2021). Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. New England Journal of Medicine, 385, 1091–1103.
- [8] Hou, X. et al. (2021). Lipid nanoparticles for mRNA delivery. Nature Reviews Materials, 6, 1078–1094.