From shield to spear: Charge-reversible nanocarriers in overcoming cancer therapy barriers

Cancer remains a significant global health burden, responsible for 16.8% of all deaths and 30.3% of premature mortality due to noncommunicable diseases, and continues to be one of the leading causes of death worldwide despite medical progress. Conventional treatment methods such as surgery, chemotherapy, and radiotherapy often face challenges such as systemic toxicity, drug resistance, and poor tumour selectivity. In response to these limitations, nanotechnology-based drug delivery systems have gained prominence for enhancing solubility, improving molecular stability, enabling controlled drug release, and prolonging systemic circulation, offering superior therapeutic outcomes over traditional approaches. Among these innovations, charge-reversible nanocarriers have attracted considerable attention due to their ability to overcome physiological and pathological barriers in the tumour microenvironment (TME) by altering their surface charge in response to specific stimuli, which enhances drug targeting while reducing off-target effects. These carriers leverage triggers such as changes in pH, enzymatic activity, redox conditions, temperature, light, ultrasound, X-rays, and magnetic fields to enable intelligent and controlled release of therapeutics. This review examines the crucial role of surface charge in cellular uptake and intracellular transport, highlighting recent advances that demonstrate improved targeting, reduced systemic toxicity, enhanced cellular internalisation, and the potential for integrated approaches, including combination therapies and theranostics. Despite these promising developments, challenges related to nanocarrier stability, safety, manufacturing scalability, and regulatory approval still impede clinical translation. Nevertheless, emerging trends in nanocarrier design, the advancement of personalised medicine, and integration with therapies (e.g., immunotherapy) underscore the transformative potential of charge-reversible nanocarriers in revolutionising cancer treatment and improving patient outcomes.