Wolf in Sheep's Clothing: Taming Cancer's Resistance with Human Serum Albumin?

Human serum albumin (HSA) has emerged as a promising carrier for nanodrug delivery, offering unique structural properties that can be engineered to overcome key challenges in cancer treatment, especially resistance to chemotherapy. This review focuses on the cellular uptake of albumin-based nanoparticles and the modifications that enhance their ability to bypass resistance mechanisms, particularly multidrug resistance type 1 (MDR1), by improving targeting to cancer cells. In our unique approach, we integrate the chemical properties of albumin, its interactions with cancer cells, and surface modifications of albumin-based delivery systems that enable to bypass resistance mechanisms, particularly those related to MDR1, and precisely target receptors on cancer cells to improve treatment efficacy. We discuss that while well-established albumin receptors such as gp60 and gp18/30 are crucial for cellular uptake and transcytosis, their biology remains underexplored, limiting their translational potential. Additionally, we explore the potential of emerging targets, such as cluster of differentiation 44 (CD44), cluster of differentiation (CD36) and transferrin receptor TfR1, as well as the advantages of using dimeric forms of albumin (dHSA) to further enhance delivery to resistant cancer cells. Drawing from clinical examples, including the success of albumin-bound paclitaxel (Abraxane) and new formulations like Pazenir and Fyarro (for Sirolimus), we identify gaps in current knowledge and propose strategies to optimize albumin-based systems. In conclusion, albumin-based nanoparticles, when tailored with appropriate modifications, have the potential to bypass multidrug resistance and improve the targeting of cancer cells. By enhancing albumin's ability to efficiently deliver therapeutic agents, these carriers represent a promising approach to addressing one of oncology's most persistent challenges, with substantial potential to improve cancer treatment outcomes.