The rational design of soft drugs has emerged as a powerful strategy to enhance drug safety, without compromising efficacy. Unlike conventional active pharmaceutical ingredients, soft drugs are deliberately designed to undergo predictable and rapid metabolic inactivation after exerting their therapeutic effect. Systemic soft drugs are particularly valuable in anaesthesiology, where rapid offset of action is desirable. Regarding topical administration, the soft drug approach enables potent local activity while minimizing systemic exposure and toxicity. However, despite these advantages and the market approval of several soft drugs, especially in dermatological, inhaled and gut-restricted therapies, the concept remains underutilized and often misunderstood, frequently being conflated with prodrugs. This Review revisits the concept of soft drugs from a modern perspective, clarifies its distinction from related approaches, highlights recent clinical successes in topical delivery, and provides practical insights into the application of soft drug design in drug discovery.

RNA-binding proteins (RBPs) are involved in every step of RNA metabolism, from RNA processing and modification to translation and decay, and are also important for the function of non-coding RNAs. As such, RBPs are crucial in shaping cell identity and are central to the development of numerous diseases. Over the past decade, systematic efforts to explore the RNA interactome have expanded the RBP census as well as the landscape of potentially therapeutically targetable RBPs. More recently, certain RBPs have been shown to be present on the cell surface with cell-type and disease-associated specificities. These cell surface RBPs could potentially serve as biomarkers and immunotherapy targets in a variety of diseases. Here, we summarize established intracellular roles for RBPs, as well as their connections to disease with an emphasis on cancer. Moreover, we review the nascent field of cell surface RBPs and describe strategies to harness the cell surface localization of RBPs for the design and development of novel immunotherapeutic modalities.

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates immunity, tissue repair and metabolic homeostasis, while also driving chronic inflammation in a broad range of diseases. IL-6 exerts its effects through distinct signalling modes, including classic signalling via its membrane-bound receptor (IL-6R) and trans-signalling via the soluble IL-6R (sIL-6R), which expands IL-6 responsiveness to most if not all cell types. Therapeutic targeting of the IL-6 pathway - primarily through monoclonal antibodies neutralizing IL-6 or IL-6R and Janus kinase (JAK) inhibitors targeting downstream signalling - has transformed the treatment of several autoimmune diseases but has also highlighted safety concerns linked to the homeostatic functions of IL-6. Advances in the understanding of IL-6 signalling biology, including endogenous regulation by soluble glycoprotein 130 kDa (sgp130) and the regulation of trans-signalling by a disintegrin and metalloproteinase 17 (ADAM17), have renewed interest in strategies that allow selective pathway modulation. In this Review, we outline the molecular basis of IL-6 signalling, examine the differential roles of classic and trans-signalling in experimental and clinical disease, and compare global and selective IL-6-targeted therapeutic approaches. We focus on the emerging concept of mechanistic and clinical differentiation within the IL-6 pathway and its implications for future drug development.

Since the turn of the century, drug discovery has been transformed by advances in genetics, genomics and proteomics, as well as automation, data science and the diversification of therapeutic modalities beyond synthetic small molecules and natural product derivatives. This transformation has led to the expansion of the drug target landscape, enabling advances in the treatment of many diseases, including some that previously lacked pharmacotherapies. In this Review, we map and quantify key elements of these changes over the past 25 years, such as trends in the number and type of targets through which drugs mediate their therapeutic effects, which now include 686 biomolecules modulated by 1,702 drugs. We also discuss trends we believe will continue or change, as target druggability continues to evolve with the emergence of new therapeutic modalities.