Biologics, such as antibodies, immunomodulators, mRNA and gene editing tools, have great potential for developing therapies with unprecedented efficacy. However, biologics still suffer from several issues that limit their application, such as poor selectivity to target tissues, impaired intracellular access and toxicity. Here, I will introduce our recent progress on the development of strategies aimed at targeted delivery of biologics by overcoming the biological barriers. These delivery approaches are based on polymeric nanocarriers that allow selective interaction with specific cells through the installation of ligand molecules and the triggered activation of the biologics’ function after sensing physiological stimuli. Thus, our strategies have shown high and selective delivery of immune checkpoint antibodies and cytokines to solid tumors, allowing increased accumulation and precise activation in response to intratumoral signals. Moreover, the nanocarriers can be engineered for promoting the intracellular delivery of biologics by promoting cellular uptake via endocytosis, allowing selective escape form the endosomes of specific cells and reaching the cytosol of these cells for therapeutic function.