Polymer nanomedicines (macromolecular therapeutics, polymer-drug conjugates, drug-free macromolecular therapeutics) are a group of biologically active compounds that are characterized by their large molecular weight. This review focuses on bioconjugates of water-soluble macromolecules with low molecular weight drugs and selected proteins. After analyzing the design principles, different structures of polymer carriers are discussed followed by the examination of the efficacy of the conjugates in animal models and challenges for their translation into the clinic. Two innovative directions in macromolecular therapeutics that depend on receptor crosslinking are highlighted: a) Combination chemotherapy of backbone degradable polymer-drug conjugates with immune checkpoint blockade by multivalent polymer peptide antagonists; and b) Drug-free macromolecular therapeutics, a new paradigm in drug delivery.