Table 1 Summary of representative TPD technologies related to different degradation pathways

Proteasome

PROTAC

Intracellular

Small molecule/

biomacromolecule/

hybrid structure

Relatively high selectivity;

Acceptable oral bioavailability;

Clear degradation mechanism;

Catalytic and sub-stoichiometric

Poor solubility for small-molecule PROTAC;

Poor cell permeability;

Poor PK properties;

Limited target spectrum

[11, 12]

Molecular glue

Intracellular

Small molecule

Acceptable oral bioavailability.

Difficult to design

[13]

SNIPER

Intracellular

Small molecule

Simultaneous degradation of POIs and IAPs;

High specificity

E3 ligase IAPs dependently

[14]

HyT

Intracellular/

extracellular

Small molecule/

Small-molecule peptide conjugate

Some hydrophobic tags are independent of E3 ligases and ubiquitination;

Wide range of potential targets;

Incomplete POIs degradation;

Unclear degradation mechanism;

Potential off-target effects

[15]

Trim-away

Intracellular

Antibody

High specificity;

Rapid degradation speed

Need extra Trim21;

Unable to recycle

[16]

Endosome-

lysosome

LYTAC

Extracellular/

membrane proteins

Antibody

Degrade extracellular and membrane proteins;

High controllability

Limited shuttle receptors;

Potential immunogenicity;

Non-catalytic;

Low degradation efficiency

[17, 18]

AbTAC

Membrane proteins

Bispecific antibody

Degrade membrane proteins;

High specificity

Large molecular weight

[19]

GlueTAC

Extracellular/

membrane proteins

Nanobody-peptide conjugate

High specificity;

Sufficient membrane permeability by a cell penetration peptide

Short half-life in vivo

[20]

Bispecific Aptamer Chimeras

Membrane proteins

Aptamer

Easy to design and prepare;

Good stability

Low delivery efficacy;

Short half-life in vivo

[21]

Sweeping antibody

Extracellular

Antibody

Allow recycling;

Required engineering for each target

[22]

Seldegs

IgG

Antigen-Fc

fusion proteins

Degrade autoantibodies;

Lower dose

Required engineering for each target;

Antigen selection

[23]

Autophagy-lysosome

CMA-based degrader

Intracellular/

membrane proteins/aggregates

Chimeric polypeptides.

High specificity;

High degradation efficacy

Low delivery efficacy;

Low stability;

Limited therapeutic effects;

[24]

AUTAC

Intracellular/

damaged organelles

Small molecule-poly(A) oligonucleotide conjugate

A wide range of potential targets;

Proteasome-independent

Low degradation speed;

Potential off-target effects;

Dependent on K63 ubiquitination;

[25]

ATTAC

Intracellular/

non-protein

Small molecule

A wide range of potential targets;

Blood-brain barrier permeability;

Difficult to design

[26, 27]

AUTOTAC

Intracellular/

protein aggregates

Small molecule

Degrade protein aggregates

Low degradation speed

[28]

Ribonuclease

RIBOTAC

RNA

Small molecule/small molecule-poly(A) oligonucleotide conjugate

Expand targeted range to RNA;

High degradation efficacy

Difficulties in finding specific ligands for targeting RNA

[29, 30]

ClpCP proteases

BacPROTAC

Bacterial proteins

Small molecule/small molecule-peptide conjugate

Expand the targeted range to bacterial protein

Low efficiency

[8]