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- Approved application/indication
Acute intermittent porphyria (AIP) (genetic disease): increased levels of the metabolites that form porphyrin (oxgen carriage).
AIP: hepatic porphyrias (when heme percursors ALA and PBG accumulate in hepatic cells)

- Active compound, type of biologics
siRNA (small interfering RNA) for knockdown of ALAS1.

- Site of action
Liver (subcutaneous injection)

- Mechanism of action
Gene Silencing of ALAS1 (siRNA).
ALAS1: delta-ALA synthase 1, which further reduces ALA and PBG metabolites.
Interaction with the dicer/HIV-1 trans-activation response RNA-binding protein (TRBP) and further with the RNA-induced silencing complex (RISC) to finally trigger the RNAi mediated gene silencing of ALAS1 messenger RNA (mRNA).
The reduced content of the ALAS1 enzyme consequently decreases the production of toxic metabolites ALA and PBG, thus counteracting a crucial underlying mechanism of porphyria
The backbone of the siRNA is modified in order to not be recognized by nucleases.

- Formulation ingredients and their role
The formulation does not utilize a nanoparticle
Three GalNac (N-acetylgalactosamine) moieties conjugated at 3'end siRNA --> binds to asialoglycoprotein receptor of hepatocytes with high affinity and specificity --> internalization in hepatocyte --> improves biodistribution to liver
Anti-ALAS1 siRNA --> active ingredient --> gene silencing
EMA excipients:
Sodium hydroxide (pH adjustment)
Phosphoric acid (pH adjustment)
Water for injections

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Active compound; Doxorubicin and Bcl-2 siRNA 

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Active compound; Doxorubicin and Bcl-2 siRNA 

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Site of action; MCF-7 breast cancer cells (adherent epithelial cell line positive for estrogen & progesteron receptors)

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Site of action; MCF-7 breast cancer cells (adherent epithelial cell line positive for estrogen & progesteron receptors)

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Approved application/indication

Covid 19

Cancer vaccine (melanoma)

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Active compound, type of biologics – lipid nanoparticles encapsulating mRNA

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Site of action- vaccines are internalized by somatic cells (for example, muscle cells) ,  tissue resident or recruited antigen presenting cells and  B cells , t cells in the lymph.

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iExosomes ( with siRNA):specific targeting KRAS
siRNA:
- siRNA binds to mRNA from oncogene expression to block translation into proteins
CD47:
- protect cells from phagocytosis of normal cells
- contributes to evasion from the host immune clearance in the circulation
RAS-mediated macropincytosis:
- facilitate the pancreatic cancer cell uptake
Protins on the surface of exosomes:
- targeting RAS

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intracellular delivery:
GalNac conjugated SiRNA will bind to asialoglycoprotein receptors on hepatic cells, enhancing internalisation and endocytosis of SiRNA

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- mutant form of GTPase KRAS in pancreatic cancer
- RAS on the surface of tumor cell

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Approved application/indication
not yet approved : Targeting of oncogenic KRAS in PDAC pancreatic ductal adenocarcinoma

- Active compound, type of biologics
Nucleic acids namely RNA interference RNAi siRNA (short interfering RNA) to reduce oncogenic Kras expression by binding to RNA molecules to block their expression.

- Formulation ingredients and their role
Exosomes with plasma membrane-like phospholipids , membrane-anchored proteins of exosomes may contribute to their diminished clearance from the circulation( CD47), - integrin functions in part to protect cells from phagocytosis, CD47 is the ligand for signal regulatory protein alpha (SIRPα), and CD47-SIRPα binding initiates the ‘don’t eat me’ signal that inhibits phagocytosis.

- Intracellular delivery strategy
exosome undergoes macropinocytosis by pancreatic tumor cells

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Mechanism of action - Spike antigens expressed in the cytoplasm are degraded by proteasomes and major histocompatibility complex (MHC) class I presents the resultant epitopes to CD8+ T cells. Spike antigens can also be endocytosed by APCs. These antigens are degraded in the lysosomes of APCs and presented by MHC II molecules for CD4+ T cells.  In addition, secreted spike antigens can be internalized by B cell receptors and processed for presentation to CD4+ T cells by MHC class II molecules.

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Formulation ingredients and their role

Ionizable lipids

protonated at low pH, which makes them positively charged, but they remain neutral at physiological pH (refs7,11,14).

- The pH-sensitivity of ionizable lipids is beneficial for mRNA delivery in vivo, because neutral lipids have less interactions with the anionic membranes of blood cells and, thus, improve the biocompatibility of lipid nanoparticles

- trapped in endosomes, in which the pH is lower than in the extracellular environment, ionizable lipids are protonated —> positively charged —> promote membrane destabilization and facilitate endosomal escape of the nanoparticles

Other copositions and their roles:

ester bond in the linker and lipidic tail of lipid carrier: increase biodegradability —> better delivery efficacy and faster elimination from the liver and plasma in vivo

- DSPC (phosphatidylcholine) with saturated tails, has a melting temperature of ~54 °C and a cylindrical geometry —>  DSPC molecules to form a lamellar phase —> stabilizes the structure of lipid nanoparticle

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Doxirubicin: could inhibit the synthesis of RNA and DNA by intercalating DNA and inhibiting the progression of the topoisomerase II, which induced the apoptosis of MCF-7 cells

Bcl-2 siRNA: suppressed the expression of key apoptosis inhibitor Bcl-2

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- Approved application/indication
* MAPKAP kinase 2 inhibitory peptide in clinical development for the prevention of fibrosis

- Active compound, type of biologics
* MAPKAP kinase 2 inhibitory peptide (with different CPP-modification)
besides biologics, nanoparticles,  gene editing (CRSIPR/Cas9) are also explored.

- Site of action
* Intracellular

- Mechanism of action
* Prevent degradation of peptide drugs

- Formulation ingredients and their role
* PPAA: PPAA interacts with and coats the cell membrane through hydrophobic interactions --> decreases the negative charge of the cell membrane --> concentrate positively charged CPPs to the cell surface and induces cellular internalization

PPAA protonation in endosome (acidic environment) --> conformation change to a more hydrophobic and membrane-active form --> reduce interactions with cationic cargo

- Intracellular delivery strategy
macropinocytosis, clathrin-mediated entocytosis

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Intracellular delivery strategy lipid nanoparticles can be internalized by multiple mechanisms, includ- ing macropinocytosis and clathrin-mediated and caveolae-mediated endocytosis

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Internalized via folate receptor-mediated endocytosis

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Endosomal escape - Although the mechanism has not yet been fully understood, positively charged lipids may facilitate electrostatic interaction and fusion with negatively charged endosomal membranes, resulting in the leak of mRNA molecules into the cytoplasm

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lipids with branched tails show enhanced endosomal escape compared with their counterparts with linear tails, owing to stronger protonation at endosomal pH

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Folate-decorated PEGylated cationic triblock copolymer:
- folate: facilitate endocytosis
The PEGylated triblock copolymer could chemically conjugate DOX onto PAH blocks via pH-responsive hydrazone bonds and simultaneously complex negatively charged Bcl-2 siRNA with cationic PDMAPMA blocks through electrostatic interactions at N/P ratios ≥ 32:1 to form multifunctional nanomicelleplexes

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Cationic polymer: important for the interaction with the ionic membrane

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Cationic polymer: important for the interaction with the ionic membrane