Chagas disease is spreading faster than expected in different countries and little progress has been reported in the discovery of new drugs to combat Trypanosoma cruzi infection in humans. Recent clinical trials have ended with small hope. The pathophysiology of this neglected disease and the genetic diversity of parasites are exceptionally complex. The only two drugs available to treat patients are far from being safe, and their efficacy in the chronic phase is still unsatisfactory. This review offers a comprehensive examination and critical review of data reported in the last 10 years, and it is focused on findings of clinical trials and data acquired in vivo in preclinical studies. The in vivo investigations classically in mice and dog models are also challenging and time-consuming to attest cure for infection. Poorly standardized protocols, availability of diagnosis methods and disease progression markers, the use of different T. cruzi strains with variable benznidazole sensitivities, and animals in different acute and chronic phases of infection contribute to it. More synchronized efforts between research groups in this field are required to put in evidence new promising substances, drug combinations, repurposing strategies, and new pharmaceutical formulations to impact the therapy.

Background: Combination chemotherapy using nanotechnology-based delivery is a promising approach to improve cancer treatment, but the added value of co-loaded polymeric nanocarriers has not been comprehensively appraised. This review synthesizes preclinical evidence on polymeric systems co-encapsulating antitumor agents. Methods: A narrative literature review identified 33 preclinical studies (2015–2025) employing polymer-based nanocarriers to co-load at least two antitumor drugs. Study characteristics and in vitro and in vivo outcomes were qualitatively analyzed. Results: Most studies addressed breast, lung, or ovarian cancer and used micelles or nanospheres. Co-loaded formulations consistently enhanced in vitro cytotoxicity and, in vivo, produced marked tumor growth inhibition relative to free drugs or single-loaded systems; in several reports, near-complete or complete tumor regression was achieved. Synergy was frequently suggested but not consistently quantified, more than half of the studies did not report a combination index. Most formulations showed favorable tolerability, with few reports including mild hepatic toxicity, renal, or weight-related effects. Beyond conventional drug pairs, examples of co-delivering chemotherapeutics with resistance modulators, gene therapy agents, or targeted ligands illustrated how tailored release profiles and active targeting can potentiate efficacy. Nevertheless, heterogeneity in models, dosing schedules, endpoints, and limited long-term safety data hamper cross-study comparison and translation. Conclusions: Co-loaded polymeric nanocarriers constitute a promising platform to optimize combination chemotherapy, improving preclinical antitumor efficacy with generally limited toxicity, but more standardized and mechanistically driven studies are required to support clinical development.