Abstract: Immunotherapy has achieved remarkable clinical success in certain cancers, particularly through adoptive cell therapy (ACT), where T cell engineering with chimeric antigen receptor (CAR) has driven major clinical breakthroughs in the treatment of hematologic malignancies. However, efficacy against solid tumors remains limited due to multiple barriers, including the scarcity of tumor-specific antigens, antigen heterogeneity, immunosuppressive tumor microenvironment, and physical obstruction of T cell infiltration by dense extracellular matrix. Nanoparticle (NP)-based approaches can overcome these obstacles and enhance ACT by improving tumor immunogenicity and vascular permeability, while reducing off-target toxicity to healthy tissues. This review discusses different strategies leveraging NPs to enhance ACT, including the delivery of immunomodulators and chemotherapeutics, NP-mediated hyperthermia, magnetic guidance to improve T cell accumulation in tumors, and in vivo NP- mediated generation and activation of CAR T cells. While prioritizing patient safety is essential, it does not fully reflect the range of risks and challenges associated with novel nanomedicines. In this regard, we discuss how integrating environmental impact assessments early in the development process is crucial for identifying key impact areas of concern and steering innovation towards more sustainable and responsible designs. Finally, we also identify current challenges, and discuss potential solutions and future research directions, including safety and sustainability
