Carrier-free nanodrugs for safe and effective cancer treatment

Clinical applications of many anti-cancer drugs are restricted due to their hydrophobic nature, requiring use of harmful organic solvents for administration, and poor selectivity and pharmacokinetics resulting in off-target toxicity and inefficient therapies. A wide variety of carrier-based nanoparticles have been developed to tackle these issues, but such strategies often fail to encapsulate drug efficiently and require significant amounts of inorganic and/or organic nanocarriers which may cause toxicity problems in the long term. Preparation of nano-formulations for the delivery of water insoluble drugs without using carriers is thus desired, requiring elegantly designed strategies for products with high quality, stability and performance. These strategies include simple self-assembly or involving chemical modifications via coupling drugs together or conjugating them with various functional molecules such as lipids, carbohydrates and photosensitizers. During nanodrugs synthesis, insertion of redox-responsive linkers and tumor targeting ligands endows them with additional characteristics like on-target delivery, and conjugation with immunotherapeutic reagents enhances immune response alongside therapeutic efficacy. This review aims to summarize the methods of making carrier-free nanodrugs from hydrophobic drug molecules, evaluating their performance, and discussing the advantages, challenges, and future development of these strategies.