Proteolysis-targeting drug delivery system (ProDDS): integrating targeted protein degradation concepts into formulation design.

Targeted protein degradation (TPD) has emerged as a revolutionary paradigm in drug discovery and development, offering a promising avenue to tackle challenging therapeutic targets. Unlike traditional drug discovery approaches that focus on inhibiting protein function, TPD aims to eliminate proteins of interest (POIs) using modular chimeric structures. This is achieved through the utilization of proteolysis-targeting chimeras (PROTACs), which redirect POIs to E3 ubiquitin ligases, rendering them for degradation by the cellular ubiquitin-proteasome system (UPS). Additionally, other TPD technologies such as lysosome-targeting chimeras (LYTACs) and autophagy-based protein degraders facilitate the transportation of proteins to  endo-lysosomal or autophagy-lysosomal pathways for degradation, respectively. Despite significant growth in preclinical TPD research, many chimeras fail to progress beyond this stage in the drug development. Various factors contribute to the limited success of TPD agents, including a significant hurdle of inadequate delivery to the target site. Integrating TPD into delivery platforms could surmount the challenges of in vivo applications of TPD strategies by reshaping their pharmacokinetics and pharmacodynamic profiles. These proteolysis-targeting drug delivery systems (ProDDSs) exhibit superior delivery performance, enhanced targetability, and reduced off-tissue side effects. In this review, we will survey the latest progress in TPD-inspired drug delivery systems, highlight the importance of introducing delivery ideas or technologies to the development of protein degraders, outline design principles of protein degrader-inspired delivery systems, discuss the current challenges, and provide an outlook on future opportunities in this field.

Cell-based relay delivery strategy in biomedical applications.

The relay delivery strategy is a two-step targeting approach based on two distinct modules in which the first step with an initiator is to artificially create a target/environment which can be targeted by the follow-up effector. This relay delivery concept creates opportunities to amplify existing or create new targeted signals through deploying initiators to enhance the accumulation efficiency of the following effector at the disease site. As the "live" medicines, cell-based therapeutics possess inherent tissue/cell homing abilities and favorable feasibility of biological and chemical modifications, endowing them the great potential in specifically interacting with diverse biological environments. All these unique capabilities make cellular products great candidates that can serve as either initiators or effectors for relay delivery strategies. In this review, we survey recent advances in relay delivery strategies with a specific focus on the roles of various cells in developing relay delivery systems.

Recent advances in biomaterial-assisted cell therapy.

With the outstanding achievement of chimeric antigen receptor (CAR)-T cell therapy in the clinic, cell-based medicines have attracted considerable attention for biomedical applications and thus generated encouraging progress. As the basic construction unit of organisms, cells harbor low immunogenicity, desirable compatibility, and a strong capability of crossing various biological barriers. However, there is still a long way to go to fix significant bottlenecks for their clinical translation, such as facile preparation, strict stability requirements, scale-up manufacturing, off-target toxicity, and affordability. The rapid development of biotechnology and engineering approaches in materials sciences has provided an ideal platform to assist cell-based therapeutics for wide application in disease treatments by overcoming these issues. Herein, we survey the most recent advances of various cells as bioactive ingredients and outline the roles of biomaterials in developing cell-based therapeutics. Besides, a perspective of cell therapies is offered with a particular focus on biomaterial-involved development of cell-based biopharmaceuticals.