As targeted protein degradation (TPD) technologies continue to redefine what is pharmaceutically actionable, emerging platforms such as AUTACs and LYTACs are pushing the boundaries beyond the proteasome. By co-opting the autophagy and lysosomal pathways, these chimeric degraders enable the selective clearance of aggregated, membrane-bound, extracellular, and even organellar targets — proteins long considered “undruggable.” With growing proof-of-concept data and accelerating innovation in ligand design, delivery, and AI-guided optimization, AUTACs and LYTACs are poised to address unmet needs in oncology, neurodegeneration, infectious disease, and rare genetic disorders. This article explores the scientific basis, therapeutic potential, and translational challenges of these next-generation degradation modalities — and why now is the moment to invest in their advancement.
Expanding the Protein Degradation Landscape
Over the past two decades, targeted protein degradation (TPD) has emerged as a transformative approach in drug development. Rather than inhibiting the function of pathogenic proteins, TPD strategies aim to eliminate them altogether, offering a way to overcome limitations associated with occupancy-driven pharmacology and expand the druggable proteome. One of the most notable advances in this field has been the development of PROTACs — proteolysis-targeting chimeras — which co-opt the ubiquitin-proteasome system to selectively degrade intracellular proteins. This modality has already advanced several candidates into clinical trials, demonstrating the therapeutic potential of hijacking endogenous degradation pathways to clear disease-driving proteins.1
Despite their promise, PROTACs have inherent limitations. Their mechanism of action restricts them to proteins located in the cytosol or nucleus, as they rely on intracellular E3 ligases to tag the target for degradation. Moreover, they are constrained by the cellular capacity of the proteasome, a degradation pathway optimized for relatively small and soluble proteins. The repertoire of proteins that can be targeted is further limited by the need for compatible E3 ligases and the ability to design high-affinity ligands for both the E3 and the protein of interest. As a result, large complexes, insoluble aggregates, membrane proteins, and extracellular targets remain largely inaccessible to this platform.
To overcome these barriers, researchers have begun exploring alternative degradation routes that exploit other components of the cell’s proteostasis machinery. Two particularly exciting classes of next-generation degraders have emerged: autophagy-targeting chimeras (AUTACs) and lysosome-targeting chimeras (LYTACs). AUTACs redirect targets to the autophagy-lysosome pathway by tagging them for selective autophagic engulfment and degradation, expanding the reach of TPD to include large protein aggregates and even organelles.2,3 LYTACs, by contrast, facilitate the internalization and lysosomal degradation of extracellular and membrane-bound proteins, addressing another major gap left by proteasome-dependent systems.4
These novel platforms complement the capabilities of PROTACs and collectively signal a broader shift in the field — from targeting only soluble intracellular proteins to enabling the degradation of diverse biomolecules across subcellular compartments and tissue types. As research continues to refine the chemistry, delivery, and specificity of these new tools, AUTACs and LYTACs are poised to play pivotal roles in expanding what is therapeutically possible.
AUTACs: Harnessing Autophagy for Targeted Clearance
AUTACs represent a novel class of chimeric molecules that leverage the cell’s autophagy machinery to degrade intracellular targets that are poorly suited to proteasome-based degradation. Structurally, an AUTAC consists of two functional domains: a target recognition moiety and an autophagy-inducing tag. The latter is often based on a guanine derivative that mimics S-guanylation, a naturally occurring posttranslational modification associated with protein degradation. Once bound to the target protein, the AUTAC recruits components of the autophagy pathway, particularly microtubule-associated protein 1 light chain 3 (LC3), which facilitates the engulfment of the tagged cargo into autophagosomes and its subsequent degradation in the lysosome.2,5,6
Initial demonstrations of this mechanism focused on the selective clearance of dysfunctional mitochondria, a process known as mitophagy. The first-generation AUTACs were shown to target and eliminate damaged mitochondria without affecting healthy organelles, validating the platform’s selectivity and providing a proof of concept for its broader applicability.2 Subsequent development led to the introduction of AUTAC4, a mitochondria-targeting chimera capable of inducing mitophagy through the same LC3-mediated autophagic pathway, further highlighting the system's modularity and therapeutic promise.3
Beyond mitochondrial quality control, AUTACs have been explored as tools for degrading aggregate-prone proteins implicated in neurodegenerative diseases, including tau and α-synuclein. These pathological proteins often resist degradation by the proteasome due to their size, aggregation state, or subcellular localization, making them ideal candidates for autophagy-based strategies. Continued work has focused on refining the linker chemistry and degradation tags to improve target engagement, cellular permeability, and degradation efficiency.7
Compared with PROTACs, which rely on ubiquitination and proteasomal degradation, AUTACs offer distinct advantages for addressing targets outside the reach of the proteasome. Their ability to degrade larger protein complexes, insoluble aggregates, and even whole organelles underscores the breadth of their potential. However, this broader capacity comes with trade-offs. Autophagic degradation is generally slower and more complex than proteasomal degradation, requiring the orchestration of multiple membrane trafficking steps. Nonetheless, AUTACs open the door to a wider class of intracellular targets, including those associated with organellar dysfunction and proteotoxic stress — conditions that lie at the heart of many chronic and neurodegenerative diseases.
LYTACs: Targeting Extracellular and Membrane Proteins via the Lysosome
While PROTACs and AUTACs have expanded the possibilities of targeted degradation within the intracellular space, a major class of disease-relevant proteins remains inaccessible to these platforms: extracellular and membrane-bound proteins. These targets, including cytokines, growth factor receptors, and immune checkpoints, are central to many pathological processes but lie outside the reach of both the proteasome and the autophagy machinery. LYTACs provide a solution by redirecting these proteins to the lysosome for degradation via receptor-mediated endocytosis.
LYTACs are bifunctional constructs composed of two functional domains. One domain binds the target protein, typically through an antibody or ligand with high specificity. The other domain engages a lysosome-trafficking receptor on the surface of the target cell, such as the cation-independent mannose-6-phosphate receptor (CI-M6PR) or the asialoglycoprotein receptor (ASGPR). Once the LYTAC brings the target into proximity with the receptor, the complex is internalized and trafficked to the lysosome for degradation.4,8 This mechanism bypasses the need for intracellular ubiquitination or proteasomal access, enabling the clearance of membrane and secreted proteins that are otherwise undruggable by traditional TPD strategies.
Since the initial proof-of-concept demonstrations, the platform has seen several refinements aimed at improving cellular uptake, trafficking efficiency, and tissue specificity. Researchers have developed synthetic glycopeptides and multivalent polymers to enhance binding to CI-M6PR and increase degradation potency.9 Another major innovation involves targeting ASGPR, a liver-specific receptor that allows LYTACs to achieve selective degradation of circulating or hepatocyte-expressed proteins. This has important implications for addressing liver-specific pathologies or minimizing off-target effects.4
Additional studies have focused on engineering the ligand components of LYTACs to optimize receptor engagement and intracellular trafficking. For example, improvements in receptor-binding motifs and linker chemistry have enhanced the efficiency of internalization and lysosomal delivery.10,11 These refinements are pushing the platform toward therapeutic relevance, enabling the design of tissue-specific degraders with favorable pharmacokinetics.
LYTACs offer several advantages that distinguish them from other TPD modalities. First and foremost is their unique ability to degrade extracellular and membrane proteins, including many clinically validated targets in oncology, immunology, and metabolic disease. Second, the use of tissue-specific lysosomal receptors such as ASGPR enables more selective delivery of degradation signals, reducing systemic exposure and potential toxicity. Finally, the compatibility of LYTACs with antibodies and other ligand classes opens the door to conjugate-based therapeutic formats, integrating the specificity of biologics with the catalytic efficiency of targeted degradation. As this technology matures, it has the potential to fill a critical gap in the TPD landscape and unlock a host of high-value targets previously deemed undruggable.
Applications and Opportunities for AUTACs and LYTACs
The broadening of the targeted protein degradation landscape through AUTACs and LYTACs unlocks new therapeutic opportunities across a diverse array of disease areas, particularly those in which pathogenic proteins lie outside the reach of proteasomal degradation. Their unique mechanisms of action, cellular access, and degradable substrates allow for intervention strategies previously unavailable through inhibition or gene silencing alone.
In neurological disorders, protein misfolding and aggregation are central pathological features. Diseases such as Huntington’s and Parkinson’s are marked by the accumulation of insoluble, toxic protein aggregates that resist clearance by the proteasome. AUTACs, by co-opting the autophagy pathway, offer a promising means of selectively targeting and degrading these aberrant protein species. Preclinical studies have demonstrated the ability of autophagy-inducing chimeras to reduce levels of mutant huntingtin and α-synuclein, providing a compelling proof of concept for the use of AUTACs in neurodegeneration.6,12 Moreover, these degraders could be paired with RNA-targeted therapies that reduce the production of toxic proteins at the transcript level, creating a two-pronged strategy for both upstream suppression and downstream clearance.
In oncology, the advantages of LYTACs are particularly pronounced. Many tumors overexpress surface receptors that drive proliferation, survival, or immune evasion, yet these proteins are inaccessible to intracellular degradation platforms. LYTACs have been engineered to degrade such receptors by leveraging lysosome-shuttling ligands, including those that bind to CI-M6PR or ASGPR. Studies have shown effective degradation of tumor-associated surface proteins, opening the door to new therapeutic approaches for solid tumors.8,10 This includes immune checkpoint proteins like PD-L1, which could be directly removed from the tumor microenvironment rather than simply blocked. Furthermore, LYTACs could be used synergistically with checkpoint inhibitors or antibody–drug conjugates (ADCs), potentially enhancing efficacy through both pharmacologic and degradative mechanisms.
Infectious diseases represent another promising frontier. Viral proteins expressed on infected cells or secreted into the extracellular space are difficult to target with conventional small molecules. LYTACs could selectively remove these pathogenic proteins from circulation or the cell surface, impairing viral replication and immune evasion. Likewise, intracellular viral components that hijack cellular machinery — such as mitochondria — could be targeted by AUTACs for selective degradation, thereby disrupting key steps in the viral life cycle.12 These strategies are particularly attractive in diseases where viral latency or persistence complicates therapeutic clearance.
In rare and genetic disorders, both platforms could offer solutions where enzyme replacement or gene therapy has proven insufficient. Many of these conditions involve the buildup of misfolded or dysfunctional proteins due to inherited mutations. AUTACs could be deployed to clear these aberrant proteins from affected cells, especially when they are prone to aggregation or organelle disruption. In lysosomal storage diseases, where certain enzymes or transporters fail to function properly, LYTACs could theoretically be designed to degrade defective proteins or modulate cellular trafficking pathways. These applications remain largely preclinical, but the underlying mechanisms align closely with the pathophysiology of many rare diseases, suggesting a strong rationale for future development.
Together, these emerging use cases illustrate the potential of AUTACs and LYTACs to go far beyond the scope of existing TPD platforms. By enabling degradation in compartments and disease contexts that were previously out of reach, they may usher in a new wave of therapeutic innovation aimed at some of the most challenging targets in medicine.
Challenges and Work to Be Done
Despite their therapeutic promise, AUTACs and LYTACs remain in the early stages of development, with several critical challenges to address before these technologies can be fully realized in the clinic. Many of the current hurdles relate not only to the novelty of the mechanisms themselves but also to the broader complexities of delivering and regulating molecules that operate outside traditional pharmacological paradigms.
One of the foremost barriers to clinical translation is the issue of delivery and molecular stability. For AUTACs, efficient cellular uptake remains a significant limitation. These chimeras must enter the cytoplasm and engage intracellular targets, yet many exhibit suboptimal permeability or are rapidly metabolized before reaching their destination. Strategies under exploration include the use of nanoparticles, lipid-based carriers, and prodrug approaches that activate within specific cellular compartments. Meanwhile, LYTACs, although designed to act on extracellular or membrane-bound targets, are limited by the dynamics of receptor-mediated endocytosis. Receptors such as CI-M6PR and ASGPR may undergo recycling or downregulation, creating bottlenecks in trafficking efficiency and reducing the amount of target that reaches the lysosome.11 Engineering more efficient receptor-binding moieties or optimizing dosing regimens may help overcome these limitations.
Another critical concern is ensuring target selectivity and minimizing off-target effects. Because these degraders co-opt cellular clearance systems that are both powerful and broad in scope, there is inherent risk in mistargeting. AUTACs that induce autophagy indiscriminately could potentially degrade essential organelles or proteins, particularly in sensitive cell types, such as neurons. Similarly, LYTACs that rely on broadly expressed lysosomal receptors might inadvertently clear non-pathogenic proteins or alter normal cell signaling. To address these risks, developers must refine the specificity of targeting ligands and consider incorporating mechanisms that restrict activity to particular tissues or cell types, such as through receptor expression patterns or conditionally activated delivery systems.
Measuring pharmacokinetics and pharmacodynamics (PK/PD) presents another set of challenges. Because AUTACs and LYTACs result in target degradation rather than inhibition, conventional occupancy-based biomarkers are insufficient. New degradomics tools are needed to track the extent, timing, and specificity of degradation events, ideally in a high-throughput and tissue-resolved manner. Quantifying the half-life of the degrader, the rate of target clearance, and the downstream functional effects are all critical for establishing dose–response relationships and therapeutic indices.
Finally, the regulatory landscape for these novel degraders is still undefined. While the success of PROTACs and ADCs has laid some groundwork for the evaluation of targeted degradation mechanisms, neither autophagy-inducing small molecules nor lysosome-shuttling chimeras have established regulatory precedents. Developers will need to engage early with agencies to define appropriate safety and efficacy endpoints, particularly given the irreversible nature of degradation and the systemic effects of modulating protein clearance pathways. Drawing on lessons from earlier degradation platforms — such as the importance of target validation, degradation efficiency thresholds, and safety pharmacology — will be key to smoothing the translational path forward.
As these obstacles are addressed through iterative preclinical development, improved analytical methods, and regulatory dialogue, AUTACs and LYTACs will be better positioned to move toward clinical evaluation. Overcoming these challenges is not only essential for realizing the therapeutic value of these platforms but will also contribute to a broader framework for evaluating the next generation of chimeric degradation technologies.
Emerging Trends and Future Directions
As the field of targeted protein degradation continues to mature, the frontier is already shifting toward the development of more sophisticated and modular degrader platforms. The innovations driving the next wave of AUTAC and LYTAC research are not only aimed at overcoming current technical limitations but also at fundamentally reimagining what degraders can do: expanding their versatility, tunability, and therapeutic reach.
One of the most intriguing developments is the concept of trifunctional degraders that incorporate elements from multiple degradation pathways. By combining autophagy-inducing motifs with proteasome-targeting components in a single molecule, researchers are exploring ways to enhance the breadth and redundancy of degradation. Such constructs could allow a single chimera to act on both soluble and aggregated forms of a protein or ensure degradation even if one pathway is impaired. This strategy may be especially valuable in diseases characterized by proteostasis imbalance, such as neurodegeneration or cancer.
Another area of innovation involves the creation of programmable degraders — molecules designed with tunable selectivity and switchable targeting profiles. Advances in synthetic chemistry and molecular recognition have enabled the design of degraders that respond to specific intracellular conditions, such as redox state, pH, or the presence of disease-associated cofactors. These "smart" degraders could remain inactive until they reach the desired environment, increasing therapeutic specificity and reducing off-target activity. Modular designs that incorporate cleavable linkers or ligand-swapping systems may also allow for the targeting of multiple proteins with a single scaffold, adjusted as needed during development or treatment.
Smart delivery systems are also playing a pivotal role in extending the utility of AUTACs and LYTACs. Nanoparticle-based carriers, ADCs, and viral vectors are being explored to improve biodistribution, cellular uptake, and tissue selectivity. These approaches are particularly promising for overcoming the delivery hurdles faced by AUTACs, which must reach the cytosol, and for enhancing the tissue specificity of LYTACs, especially when targeting receptors like ASGPR for liver-directed therapies. Incorporating targeting ligands into delivery systems may also help address safety concerns by confining degrader activity to relevant cell populations.
Perhaps most transformative is the growing convergence between degrader design and artificial intelligence (AI)-driven drug discovery. AI models trained on structure–activity relationships, protein–ligand binding data, and degradation outcomes are being used to predict optimal degrader configurations. These tools can assist in linker design, tag placement, and receptor-binding domain optimization, greatly accelerating the iterative design process. Early efforts have shown promise in generating novel AUTAC and LYTAC candidates with improved potency and selectivity using AI-guided platforms.13
Together, these emerging trends suggest a future in which degraders are no longer static chemical entities but dynamic, programmable tools that can be tailored to the complexities of each disease and patient. As AUTACs and LYTACs evolve alongside advancements in delivery, data science, and systems biology, they are poised to play a foundational role in the next generation of precision therapeutics.
The Next Evolution of Targeted Degradation
AUTACs and LYTACs represent the next logical expansion of targeted protein degradation, extending the reach of this modality well beyond the cytosolic and nuclear proteins accessible to PROTACs. By harnessing the cell’s autophagy and lysosomal pathways, these platforms allow for the selective clearance of targets that were previously considered undruggable, including large protein aggregates, dysfunctional organelles, membrane-bound receptors, and extracellular factors. Their mechanisms open up new possibilities in treating neurodegenerative diseases, solid tumors, chronic viral infections, and rare genetic disorders — areas where existing therapeutic options are limited or ineffective.
The ability of AUTACs to address intracellular accumulation and organellar damage and that of LYTACs to engage extracellular and surface proteins with tissue specificity offer a complementary toolkit for reshaping therapeutic strategies across disease areas. With continued innovation in molecular design, delivery technologies, and tissue targeting, these chimeras are poised to become integral components of precision medicine, especially for conditions that resist traditional inhibitors or are not yet addressable by gene or cell therapies.
As the field learned with the rise of PROTACs, early skepticism often gives way to clinical promise when foundational science is paired with practical investment and translational vision. The window is now open to build on the mechanistic insights and early proof-of-concept studies in AUTACs and LYTACs, accelerating their path toward therapeutic reality. By supporting this new generation of degraders with the same rigor and creativity that drove the success of earlier platforms, the industry has an opportunity to unlock a broader, more versatile, and ultimately more effective approach to targeted protein modulation.
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